diversity and dialogue in immunity to helminths

8/2/2019 Diversity and Dialogue in Immunity to Helminths

1/14

The immune system has evoved to defend us from thefu spectrum of pathogens, incuding microorganisms,such as viruses, bacteria, fungi and protozoa parasites,and macropathogens, such as muticeuar heminths andectoparasites. Each of these pathogens poses a very different probem for the immune system to resove and, correspondingy, we have evoved speciaized mechanisms andce popuations to best address the chaenge encounteredin each setting. When operating optimay, the immunesystem interweaves the innate and adaptive arms of immunity, at both sensitization and effector eves, in a continuous diaogue that seects, caibrates and terminates theresponse in the most appropriate manner. Many pathogens, however, have deveoped compex evasion strategies and, when the immune response fas short, it may benecessary for the host to enter a damage imitation state,accommodating infection in order to minimize pathoogy.Moreover, most parasite immune evasion mechanismsthemseves depend on a form of moecuar diaogue

between pathogen and host and, in turn, many parasitesdepend on host moecuar signas for their deveopment.

The variety of parasite ife histories, and the fineyevoved evasion strategies of different pathogens (whichtarget the fu range of host immune pathways), are ikeyto have driven diversification and redundancy withinthe immune system to generate aternative mechanismsand dupicate key functions that are essentia to surviveinfection. For exampe, the adaptive T heper 2 (T

H2)

ce response that is typica of heminth infections ismirrored by a range of innate helper cell responses1,2.Thus, mutipe ce types contribute crucia cytokinesto enhance T

H2type immunity3,4, and overapping

popuations of reguatory ces can execute simiar functions5, guided by the overa stimuatory miieu. Thesetopics are discussed in detai in this Review.

Type 2 immunity

Unike bacteria, protozoa, fungi and viruses, mostheminths do not repicate in the mammaian host. Theinfective stages must estabish infection and then growto sexua maturity, producing eggs or ive offspringfor transmission to the next host. The adut stages ofthese parasites can ive for decades inured to immunemediated attack. These distinct features, as we as themuticeuar nature of these pathogens, may expain whyheminths induce an entirey distinct immune responseprofie from microbia pathogens. In both humans andanimas, this canonica response is of the T

H2 type and

invoves the cytokines intereukin3 (IL3), IL4, IL5,IL9, IL10 and IL13, the antibody isotypes IgG1, IgG4and IgE, and expanded popuations of eosinophis,

basophis, mast ces and aternativey activated macrophages68. The innate immune system not ony anticipatesand initiates the adaptive T

H2 ce response but, impor

tanty, continues to provide accompanying and mutuayreinforcing pathways of T

H2type immunity throughout

infection1,2,9. This paraeism no doubt refects both theancient evoutionary origin of T

H2type immunity and

the imperative to mount this mode of response in manydifferent circumstances, not east of which is infectionwith heminth parasites. As many nonT ces, especiayinnate ces, are important contributors to the T

H2 ce

dominated response, we refer in this Review to a gobatype 2 immunity that encompasses a of these payers.

Institute for Immunology

and Infection Research,

Ashworth Laboratories,

West Mains Road,

University of Edinburgh, UK.

Correspondence to R.M.M.

email: [email protected]

Both authors contributed

equally to this work.

doi:10.1038/nri2992

Innate helper cell

A lymphoid cell that lacks

antigen-specific receptors

(such as B or T cell receptors)

but that has the capacity to

make cytokines associated

with T helper (TH) cells(for example, the T

H2-type

cytokines interleukin-4 (IL-4),

IL-5 and IL-13) in response to

innate alarm cytokines, such

as IL-25 and IL-33.

Diversity and dialogue in immunityto helminths

Judith E. Allen and Rick M. Maizels

Abstract | The vertebrate immune system has evolved in concert with a broad range of

infectious agents, including ubiquitous helminth (worm) parasites. The constant pressure of

helminth infections has been a powerful force in shaping not only how immunity is initiated

and maintained, but also how the body self-regulates and controls untoward immune

responses to minimize overall harm. In this Review, we discuss recent advances in definingthe immune cell types and molecules that are mobilized in response to helminth infection.

Finally, we more broadly consider how these immunological players are blended and

regulated in order to accommodate persistent infection or to mount a vigorous protective

response and achieve sterile immunity.

REVIEWS

NATURE REVIEWS |IMMUNOLOGY VOLUME 11 | JUNE 2011 |375

2011 Macmillan Publishers Limited. All rights reserved
mailto:[email protected]:[email protected]


2/14

The centra payer in type 2 immunity is certainythe CD4+ T

H2 ce, which expresses some or most of

the cytokines isted above, as we as key chemokines,such as the CCchemokine receptor 3 (CCR3) igandCCchemokine igand 11 (CCL11; aso known aseotaxin 1). In cassic studies, mice depeted of CD4+ cesdid not mount a protective immune response foowing

vaccination with Schistosoma mansoni10 and acked theabiity to expe the intestina heminth Nippostrongylusbrasiliensis 11. However, transfer of IL4expressingCD4+ ces ed to worm expusion in T cedeficientmice12. Furthermore, deficiencies in key signaing moecues associated with type 2 immune ces increase the

susceptibiity of mice to infection with heminths, andmice acking the IL4 receptor chain (IL4R), signatransducer and activator of transcription 6 (STAT6)13or the transcription factor GATAbinding protein 3(GATA3)14 show highy compromised antiheminthimmunity.

IL4R, which is a component of both the IL4 andIL13 receptors, is in fact the nexus of type 2 immunity(FIG. 1), as shown by the suite of effector mechanismsdriven by IL4 and/or IL13. These two key inducercytokines can be produced by innate as we as adaptive immune ces, with innate IL4 and IL13 beingrequired for timey expusion ofN. brasiliensis15. Recent

Figure 1 | IL4Ris at the centre of type 2 immunity. The central role of the interleukin-4 receptor -chain (IL-4R) fortype 2 immunity is illustrated. IL4R may combine with the common -chain (

c) or IL-13R1 to bind IL-4 alone, or both

IL4 and IL13, respectively. The relative potency of IL4 and IL13 in signalling through the type II receptor

(IL-4RIL-13R1) may depend on the surface concentrations of each receptor subunit, with IL-13 being more effectivethan IL-4 at inducing receptor signalling when the levels of IL-13R are low169. CCL11, CC-chemokine ligand 11;DC, dendritic cell; MBP, eosinophil granule major basic protein; MUC5AC, mucin 5AC; RELM, resistinlike molecule;

ROS, reactive oxygen species; TSLP, thymic stromal lymphopoietin; TH2, T helper 2.

REVIEWS

376 | JUNE 2011 | VOLUME 11 www.nature.com/reviews/immunol



3/14

NonB, nonT cells

(NBNT cells). Cells that are

distinct from immunoglobulin-

or T cell receptor-bearing

lymphocytes, basophils,

eosinophils, mast cells andnatural killer T cells and can

produce T helper 2 (TH2)-type

cytokines.

Tight junctions

A tight junction is a belt-like

region of adhesion between

adjacent epithelial or

endothelial cells that regulates

paracellular flux. Tight-junction

proteins include the integral

membrane proteins occludin

and claudin, in association

with cytoplasmic zonula

occludens proteins.

studies of IL4 and IL13 expression patterns inmicehave shown that significant numbers of cytokineproducing non-B, non-T cells (NBNT ces) are foundduring heminth infection1619. In particuar, this workhas highighted the contribution of a new type of innateheper ce (aso termed a nuocyte or natura heperce) that is among the first to produce type 2 cytokinesfoowing heminth infection. These ces create conditions that favour T

H2 ce induction and, after receiv

ing signas from differentiated TH

2 ces, they continueto reease IL13 and promote type 2 immunity. In theabsence of these innate heper ces (for exampe, inIL25deficient mice, as discussed in detai beow), T

H2

ce immune responses during heminth infection aregreaty impaired.

Irrespective of their ceuar source, type 2 cytokinesmobiize a broad range of downstream effector mechanisms8(FIG. 2). In the gut, epitheia ces express IL4Rand act both as key sentines20 and as responders topromote gobet ce differentiation, the enhancementof mucus secretion21 and the production of resistinike

moecue (RELM), which is an innate protein withdirect antiheminth activity22,23. In addition, IL4Rigation stimuates intestina musce hypercontractiity24 and acceerated epitheia turnover25 to promote theepitheia escaator, which functions together with epitheia secretions to disodge resident parasites. Mucosamast ces mutipy in the infected gut in response toIL9 (REF. 26) and IL18 (REF. 27) and reease mast ceproteases that can degrade tight junctions, therebyincreasing fuid fow as part of the weep and sweepresponse. IL4 and IL13 aso drive the aternative acti

vation of macrophages, and this is impicated in trapping Heligmosomoides polygyrus in the gut wa28. As theheminth worm is severa orders of magnitude arger thanany host ce, macrophagemediated kiing of heminthsmay be a protracted affair, in which these ces impose asow death by compromising worm vitaity rather thanproviding an immediate etha hit.

In nonmucosa tissues, parasites must be destroyedrather than excuded, and the type 2 response is consequenty very different. In the tissues, effector mechanisms can invove the fu panopy of innate immuneces in different settings8, with antibody aso actingto arm Fc receptor (FcR)expressing effector ces.Basophis produce high eves of IL4 to drive T

H2type

responses during both mouse29 and human30 heminthiasis, and act as effectors to promote parasite kiing

during chaenge infections of immunized animas31,32.However, basophis are not essentia for the cearance ofprimaryN. brasiliensis infection33, perhaps as they arenot sufficienty armed with parasitespecific antibodyat that point. Athough eosinophis can prove cruciain producing eary IL4 (REF. 34), they are generayparticipants and ampifiers of immunity rather thanindispensabe payers15,35,36. Simiary, neutrophis canaso attack heminth arvae in response to IL4 and IL5(REFS 37,38), but the reative importance of each hostce type depends on both the tissue in question andthe differentia susceptibiities of individua heminthspecies to attack. Often, the most important tissue site in

terms of heminth immunity is the ung: this is the focapoint traversed by schistosome, hookworm and othermigrating arvae, and CD4+ T cedependent immunitycan be initiated here39. In addition, the ung is a potentocae for the IL4Rdependent aternative activation of macrophages, which then produce arginase 1,chitinase 3ike proteins 3 and 4 (aso known as YM1 andYM2, respectivey) and RELM (rather than RELM,which is a product of epitheia ces in the gut)40,41.

The humora profie of TH

2type immunity centres on the eevation of the eves of IgG1, IgE and (inhumans) IgG4 isotype antibodies. Athough these isotypes are dependent on cytokines that can be derivedfrom both innate and adaptive sources (namey,IL4 and (in the case of IgG4) IL10 (REF. 42)), innateheper ces cannot substitute for T ces in providingCD40mediated costimuation of B ces. Antibodiesare particuary important for mediating protectionagainst the extraintestina stages of heminth infections,incuding the encysted stages of intestina parasites43.On the other hand, B ce or immunogobuindeficient

mice show ony minor differences in susceptibiity tomost primary heminth infections compared with contro mice, athough antibodies act to reduce the fitnessofH. polygyrus44. In humans45 and sheep46, there is agood association between IgE production and acquiredimmunity to heminth infections, but evidence in miceis more imited, perhaps owing to poor expression ofthe highaffinity IgE receptor on mouse eosinophis47.Nonetheess, there is in vitro evidence that IgE can kiheminth arva stages through antibodydependentceuar cytotoxicity mechanisms48, and both eosinophisand IgE are required for vaccinemediated protectionagainst arva Onchocerca volvulus in mice49. Thus, IgEmay be a crucia means by which incoming arvae arekied during concomitant or secondary infection.

There are important subteties, in both antibodyand cytokine responses, in the mix and baance of theT

H2type response. High IgG4 eves, and depressed

IgE eves, are seen both in chronic human heminthinfections, in which effector immunity is muted 50,and in desensitized aergy patients, in whom a modified IgG4dominated T

H2type response is associated

with the resoution of symptoms51. Moreover, in somespecific instances immunity to heminths does notrequire the T

H2 ce pathway at a, being more T

H1 ce

dependent5254.

Why did type 2 immunity evolve?The crucia roe for T

H2 ces in protection against

heminths suggests that type 2 immunity is the evoutionariy appropriate response to worms. Indeed, exposure to any arge metazoan, incuding ectoparasites,can trigger a T

H2type immune response and its down

stream consequences55, but how did a distinct pathwayfor muticeuar pathogens evove? Cassica T

H1 ce

induced infammatory mediators certainy damageworms56, but at a substantia cost in coatera damage tohost tissue. Ceary, macropathogens cause extensivetissue disruption whie migrating through the host.Thus, in evoutionary terms, type 2 immunity may have

REVIEWS




4/14

arisen from our innate response to tissue injury, withrepair responses isoating and encapsuating macroparasites through the deposition of extraceuar matrix proteins whie simutaneousy resoving ocaized damage57(FIG. 3). Many facets of antiheminth immunity, such asmucus production by epitheia surfaces, are consistentwith evoutionary origins in woundheaing pathways58.

Furthermore, IgE functions argey through its abiity tobind to eosinophis and mast ces, which are both majorpayers in the response to tissue injury59,60. This suggests that during the evoution of the adaptive immunesystem, antibody isotypes that enhanced resistance toheminths (or indeed, arthropod ectoparasites) werespecificay taiored to work with ces invoved in repair.

Figure 2 | TH2type effector mechanisms in immunity to helminths. Pathways of immune clearance mediated by

T helper 2 (TH2) cells are more clearly defined in the intestinal setting than in the tissues, but in both instances multiple

mechanisms come into play. a | In mucosal immunity to helminths, TH2type responses are initiated and sustained by

innate populations (including the epithelial cell layer) through interleukin25 (IL25) and IL33 (REF. 19). Epithelial cells

are also one of the principal targets of TH2type cytokines, as IL13 increases cell turnover (resulting in the epithelial

escalator)25 and induces the differentiation of goblet cells, which produce mucins and the anti-nematode protein

resistin-like molecule- (RELM)21,22. Fluid transfer into the gut is raised by the action of mast cell proteases, whichdegrade tight junctions in the epithelial cell layer26, adding to the weep and sweep process. Antibodies from B cells also

contribute by diminishing worm fitness and fecundity43. b | In the tissues, parasites are open to attack by the full range of

host innate effectors, including macrophages7, neutrophils37, eosinophils170, basophils31 and platelets171 (not shown). The

ability of these effector cells to kill helminths is often dependent on one or more isotypes of specific antibody (often IgE,but IgM in the bloodstream) and complement. Armed granulocytes or macrophages can release damaging metabolic

oxygen and nitrogen intermediates onto helminths, but in vivo killing methods are not yet fully understood. CXCR2,

CXCchemokine receptor 2; FcR, Fc receptor; IL4R, IL4 receptor.

REVIEWS




5/14

IgE may aso have evoved to provide a mechanism forparasite contro that reduces the risk of sef damage,because it fais to activate compement, a major mediatorof autoimmune disease.

The antiinfammatory nature of type 2 immunityis consistent with tissue repair pathways because cassica infammation must be controed before heaingcan be initiated61. This is iustrated by the dua antiinfammatory and wound heaing functions of T

H2type

cytokines, such as transforming growth factor (TGF).Indeed, chronic microbia infections that cannot be fuycontroed by T

H1 or T

H17type immune responses

progressivey induce more TH2type responses, which

dampen infammatory damage, repair injured tissueand restore homeostasis62. Strongy inked with T

H2type

responses are other factors that maintain homeostasis inthe face of macropathogen assaut, such as the productionof toxinspecific neutraizing antibodies63. Importanty,the association of type 2 immunity with woundingand the maintenance of homeostasis can aso be observedin fish such as Atantic samon (Salmo salar)64.

Athough heaing appears to be argey norma inmice that are deficient in key components required fortype 2 immunity, subte differences are emerging, mostnotaby in the rate of repair 57,65. T

H2 cemediated rapid

repair may be essentia when the organism or tissue cannot afford to wait for a sow heaing process; for exampe,when gut integrity is compromised by a boodfeedinghookworm. The association of IL13 and, in particuar,aternativey activated macrophages with scar tissue suggests that perhaps T

H2type responses promote repair

that is fast and dirty, aowing rapid wound cosure atthe cost of fu tissue integrity57. T

H2type responses can

induce proteins that are associated with injury or repair such as arachidonate 12ipoxygenase and arachidonate 15ipoxygenase, triggering receptor expressed onmyeoid ces 2 (TREM2), arginase 1 and RELM proteins and many of these proteins aso have roes in downreguating infammation and/or in parasite kiing6570.Thus, type 2 immunity has three major components:wound repair, infammatory contro and heminth resistance, a of which combine to maintain homeostasis inthe infected host.

Innate initiation of the TH2type response

Evoutionary considerations may address a majorunknown: how the immune system is aerted to thepresence of heminths and can appropriatey seect

the TH2type pathway of immunity. In contrast to thearchetypa Toike receptor (TLR)mediated, IL12promoted stimuation of T

H1type immune responses71

and the dectinresponsive, speen tyrosine kinase(SYK)mediated initiation of the T

H17 ce pathway72, the

inception of TH2 ce differentiation is not understood.

Earier hypotheses that TH2type responses represented

a defaut state, resuting from suboptima stimuation,did not account for heminth antigens that show dominant T

H2 cepromoting activity in a T

H1 cefavouring

immune environment73,74. As the TH2type outcome is

amost universa in heminth infections, one suspectsthe invovement of a parae, conserved recognition

pathway that is responsive to metazoan moecuar signatures, perhaps those associated with the potentia ofthese organisms to induce tissue injury75. Consistentwith this, tissue injury aone is sufficient to induce innatetype 2 responses76.

Exciting and reevant deveopments have highighted the importance of mucosa epitheia ces forthe initiation of type 2 immunity. Athough it is sefevident that the barrier ayer is the first to be exposedto, or breached by, pathogens, we have recognized onyrecenty the unique sensitivity of the intestina epitheium (for exampe, through the identification of TLRexpression) and its capacity to raise the aarm throughthe production of IL25, IL33 and thymic stroma ymphopoietin (TSLP)20. Aarmdriven innate ymphocytesare then recruited and reease IL4 and IL13, therebypromoting an eary T

H2skewed response4. The newy

differentiated TH2 ces feed back (through an unidenti

fied pathway) to maintain the innate heper ce popuations, and aso drive gobet ce differentiation and theproduction of mucus and RELM within the epitheia

ayer. Thus, innate IL25 production not ony stimuatesIL13 production from innate heper ces but is furtherpromoted by IL13 in a positive circuit that maximizesthe T

H2type response77.

In keeping with the proteoytic activity of tissuemigrating heminths, proteases have been consistentyimpicated in T

H2 ce activation and can directy induce

epitheia ces to produce TSLP78, one of the TH

2 ceinducing aarmins. Indeed, the defining feature of theaarmin cytokines is their abiity to aert the immunesystem to tissue injury. For exampe, functionay activeIL33, another potent inducer of T

H2type cytokines,

is reeased from the nuceus foowing necrotic but notapoptotic ce death of fibrobasts, endotheia ces andepitheia ces79.

However, tissue injury aone does not induce fuT

H2 ce activation76, whereas soube heminth products

can8082. TH2 ceinducing heminthderived moecues

have been described, but we are sti mosty ignorant ofthe nature of these moecues and of the receptors thatpresumaby exist on innate immune ces to recognizeheminth products. The fact that T

H2type responses

are intact in the absence of myeoid differentiation primary response protein 88 (MYD88) and TIRdomaincontaining adaptor protein inducing IFN (TRIF)83,84argues that the initiation of T

H2type immunity is

independent of, if not totay unconnected to, the TLR

system. Some eary indications are that Ctype ectinreceptors (CLRs) igate heminth gycans85, activatingthe SYK intraceuar pathway in the case of schistosomeegg antigens (SEAs) and the CLR dectin 2 (aso knownas CLEC6A)86. The identification of the SEAderivedantigen omega 1 (REFS 81,84) as an intrinsic driver of theT

H2type response may now carify a receptor pathway

on innate ces responsibe for this crucia decision.Athough the moecuar events remain obscure, the

stimuation of TH2 ce differentiation has been attributed

to a diverse range of ce types, incuding most recentyand controversiay basophis, which were reported to beabe to induce T

H2 ce responses in vitro and in vivo87.

REVIEWS




6/14

Recombination activatinggene (RAG)deficient mice

Recombination activating

genes are involved in creating

the double strand DNA breaks

necessary for producing the

rearranged gene segments that

encode the complete protein

chains of T cell and B cell

receptors. Mice that are

deficient for these genes fail to

produce B and T cells owing to

a developmental block in the

gene rearrangement that is

necessary for antigen receptor

expression.

However, athough in vivo depetion of dendritic ces(DCs) inhibits the induction of a T

H2type immune

response to S. mansoni, TH

2 ce differentiation inresponse to this pathogen is not affected by basophidepetion88. Hence, as shown by adoptive transferof heminthpused DCs73,89, the adaptive T

H2type

response is dependent on and driven by conventionaDC popuations. In human DCs too, exposure to SEAseads, via CLR recognition, to the induction of T

H2

ces85. Taken together, these data demonstrate that DCsaone can drive T

H2 ce differentiation, even when other

innate popuations have not been exposed to heminths.Basophis, therefore, may ony rarey be responsibe for

the initiation of TH2type immunity against heminths87,and their main roe coud instead be to ampifythe type 2 response30,90. With intensifying interest in theheminthDC interface (reviewed in REF. 91), the outstanding issue is now to identify which particuar DCsignas induce the T

H2 ce differentiation programme

in naive T ces92.

Duplication and diversity in type 2 immunity

The controversy over the roe of basophis in TH

2 ceinduction may iustrate a more genera point that theimmune system has repeatedy dupicated and redupicated essentia functions, generating widespread

operationa redundancy. Hence, identifying the physioogicay important ce popuation (or the particuarcytokine) necessary for T

H2type immunity is highy

context dependent, with the type 2 response itsefincorporating both the innate and adaptive arms ofthe immune system, mirroring the important roesof both natura kier (NK) ces and T

H1 ces in

interferon (IFN) production. For exampe, wormexpusion normay requires the presence of T

H2 ces,

but exogenous IL25 or IL33 can induce sufficientIL13 production from innate heper cesto stimuategobet cedependent worm expusion in the intestina epitheium16. Simiary, innate sources of IL4 and

IL13 drive fu aternative macrophage activation inrecombination activating gene (RAG)-deficient mice41,76, butCD4+ T ces are needed for sustained activation duringchronic heminth infection76. Often, then, the innateimmune system offers a ess potent force, but one thatmaintains a cose parae to the adaptive response.

The requirement for T ce icensing of ongoinginnate reactivity imposes an inherent imitation onthe innate type 2 response, ensuring that it is appropriatey caibrated and directed in vivo. Furthermore,mutipe ce types participate in responding to IL13and in ampifying type 2 immune responses; for exampe, even when ony smooth musce ces fai to express

Figure 3 |Type 2 immunity in the repair of parasiteinduced damage. Parasites such as hookworms repeatedly breach

the gut wall, and the resulting cell death leads to the release of alarmins, such as interleukin-33 (IL-33). These molecules,

along with parasite products, promote a type 2 response, either directly by acting on innate cells or indirectly through

antigenpresenting cells (APCs) that induce T helper 2 (TH2) cells. Macrophages in this setting may be predominantly

antiinflammatory, suppressing T cell responses through arginase 1 production and inhibiting classical macrophage

inflammation and recruitment through the production of arginase 1, triggering receptor expressed on myeloid cells 2

(TREM2) and other molecules. Epithelial cells stimulated by TH2type cytokines can induce resistinlike molecule (RELM)

or RELM, which contribute to wound repair, while arginase 1 from fibroblasts may promote extracellular matrix (ECM)deposition that can either repair damage or encapsulate worms. ES, excretory secretory.

REVIEWS




7/14

Anergy

A state of unresponsiveness

that is sometimes observed in

T and B cells that are

chronically stimulated or are

stimulated through the antigen

receptor in the absence of

co-stimulatory signals.

IL4R, gobet ce hyperpasia is diminished and expusion ofN. brasiliensis is significanty deayed93. TSLPiustrates a further exampe of the highy contextdependent nature of ceuar crosstak in T

H2type

immunity. TSLP sensitizes DCs to promote a TH2 ce

deveopmenta pathway, but athough the TSLPDCdiaogue is essentia for T

H2type immunity to Trichuris

muris94 it is not required for TH

2type responses toother intestina nematodes, such as H. polygyrus andN. brasiliensis95. This perhaps refects the fact thatthe T

H1/T

H2 dichotomy is more finey baanced in

T. muris infection, whereas during other heminthinfections TSLP may act as an enhancer rather thanas an essentia stimuus of type 2 immunity. In addition, the fact that H. polygyrus and N. brasiliensis canmimic the activity of TSLP and bock DC production of IL12p70 (REFS 73,96) coud expain why TSLPis not essentia for T

H2 ce deveopment foowing

infection with these species.This mix of redundancy and diversification is fur

ther seen in the broad range of ces targeted by type 2

cytokines. Athough basophis, eosinophis, mast ces,neutrophis and macrophages each express a specificset of effector moecues, they aso share expressionof a number of proteins associated with type 2 immunity, such as chitinase 3ike protein 3, RELM andarginase 1. These moecues are aso expressed bysevera nonhaematopoietic ces, in particuar epitheia ces. However, expression patterns (of both RNAand protein) differ depending on the tissue ocaizationand the stage of infection7. The chaenge wi be todetermine when proteins have cespecific as opposedto redundant roes. For exampe, arginase 1 can suppress fibrosis, but this function is ost when the arginase 1 gene is specificay deeted in macrophages69,suggesting that arginase 1 may be antiinfammatorywhen produced by macrophages but have tissue reparative functions when produced by fibrobasts. Simiary,the immune suppressive properties of RELM68,70may be confined to RELM produced by antigenpresenting ces (APCs), with epitheia ce productionof RELM being more important for tissue remodeing. Thus, consistent with their expression of IL10(REF. 97), TGF98 and programmed ce death 1 igand 2(PDL2)99,100, aternativey activated macrophages mayhave a predominant reguatory roe. But when proteinsexpressed by aternativey activated macrophages (suchas arginase 1 or RELM) are produced in a different

tissue or in the absence of IL10, these proteins maypromote effector immune functions, such as repairor parasite kiing. Determining whether moecuesexhibit contextspecific or cespecific functions isparticuary important for the transation of researchfindings to the treatment of human disease, as thehuman ceuar expression patterns of many proteinsare fundamentay different from those in mice. Forexampe, neutrophis rather than monocytes and macrophages are the primary source of constitutive arginase 1expression in humans101, but human monocytes havebeen observed to produce arginase 1 during patentinfection with Brugia malayi 102.

Selection, competition and anergy among T cells

Despite the dominant TH2 ce phenotype evident in

heminth infections, other CD4+ T ce popuations canexpand during these infections and the T

H2 ce popu

ation may diminish over time. This ebb and fow mayrefect constant competition between T

Hce subsets,

either for the same poo of naive T ce precursors or,subsequenty, in the choice of more speciaized outcomes, such as differentiation into T foicuar heper(T

FH) ces103 or T

H9 ces, which can arise foowing

combined stimuation with IL4 and TGF104. Fate competition can aso operate when ces that are consideredto be committed to a particuar T

Hce subset are, in

fact, reativey pastic and abe to switch phenotypeunder the infuence of a differing cytokine miieu 105.In many infections, T

H2 ce dominance is maintained

by IL10mediated suppression of competing TH1 and

TH

17 ce popuations106, refecting the roe of IL10as a necessary component of the T

H2 ce response to

heminth infections107. The importance of this can beseen in schistosomeinfected CBA mice, in which this

reguatory network fais and exacerbated pathoogyoccurs owing to increased T

H17 ce activity against the

schistosome eggs, in pace of the TH2type response gen

erated in other mouse strains108. Many other potentiainteractions between T

H2type immunity and nonCD4+

T ce subsets have yet to be propery expored duringheminth infections, athough the expansion of CD8+T ce109 and natura kier T (NKT)110 ce popuationsis known to occur in many instances.

When the immune system fais to reject parasites anda chronic infection takes hod, the T ce compartmentchanges more with regard to its state of responsivenessthan in its composition of T

Hce subsets. Cassic stud

ies on schistosomiasis documented the diminution ofhepatic granuomas as the immune response subsides inchronicay infected mice111. A parae is ceary seen inchronic human heminth infections, in which a T

H2 ce

dominated immune profie, with high eves of IL4 andIL10 production, is accompanied by a muted IL5and IL13 response and an overa oss of T ce proiferative responses towards parasite and bystander antigens50,112. This is suggested to represent a modifiedT

H2type response, as discussed above. The host immune

system can thus be in a state of effective toerance eventhough many key markers of T

H2type immunity are

sti evident.In human fiariasis and in a mouse fiariasis mode

using Litomosoides sigmodontis, the chronic phase ofinfection is marked by T ce anergy, oss of proiferativeresponses to parasite antigen chaenge, reductions ineffector cytokine eves and eevated expression of inhibitory immune moecues, such as cytotoxic T ymphocyte antigen 4 (CTLA4). In the mouse mode, parasitesurviva is inked to reguatory T (T

Reg) ce activity

(see beow), and immunity to infection can be boostedony if T

Regce depetion is accompanied by deivery of

CTLA4specific bocking antibodies or gucocorticoidinduced TNFRreated protein (GITR)specific stimuatory antibodies to restimuate the anergized effectorT ce popuations113,114. Simiary, anergic T ces are

REVIEWS




8/14

Regulatory B cells

Populations of B cells that

downregulate immune

responses. These cells are

most often associated withproduction of the

immunosuppressive cytokine

interleukin-10.

T regulatory type 1 cells

(TR1 cells). A subset of CD4+

regulatory T cells that secrete

high levels of interleukin-10

(IL-10) and downregulate T

helper 1 (TH1) and T

H2 cell

responses in vitro and in vivo

by a contact-independent

mechanism mediated by the

secretion of soluble IL-10 and

transforming growth factor-.

found in both humans115 and mice with schistosomiasisand, in the atter case, these T ces express the anergyprotein GRAIL (gene reated to anergy in ymphocytes;aso known as RNF128)116. Interestingy, anergy induction in murine schistosomiasis, as in fiariasis, is inkedto a coinhibitory signaing pathway, in this case viaPDL1 interactions117. In humans, if the anergic phenotype is not imprinted on the memory T ce popuations,then foowing curative drug therapy it may be possibeto reset the T ce compartment to generate protectiveimmunity. New immunoogica strategies, particuarythose aimed at neutraizing reguatory popuations, mayachieve this goa.

Regulation: the crucial factor

Human heminth infections exhibit many immunedownreguatory phenomena, with heminthinfectedpopuations showing ower eves of immunopathoogica disease in cohort studies of aergy and autoimmunity.Mode system studies have inked heminth infectionswith marked expansion of popuations of immuno

reguatory ces, such as aternativey activated macrophages, T

Regces and regulatory B cells. For exampe, in

H. polygyrusinfected mice, forkhead box P3 (FOXP3)+T

Regces are not ony present in greater frequencies than

in naive animas, but they aso express higher eves ofCD103 and are more potent immune suppressors thanT

Regces from uninfected mice118,119. Moreover, many

aergic and autoimmune infammatory conditions canbe ameiorated by a range of different heminth infections120123. One key question is whether reguatory cesare simpy reacting homeostaticay to contro heminthinduced pathoogy. As ive, but not dead, parasites canexpand T

Regce popuations124 and parasites secrete fac

tors that directy induce the conversion of naive T cesinto functiona T

Regces125, we concude that the activation

of reguatory pathways in response to parasite infectiondoes not soey refect the immune systems response toinfammation associated with infection.

Accordingy, evidence from humans and mousemodes argues for a major roe of CD25 +FOXP3+T

Regces in controing pathoogy and immunity dur

ing heminth infections. In patients with fiariasis,heminthinduced pathoogy is associated with a deficiency in CD25+FOXP3+ T

Regces126, and intestina

nematode infection eves correate with both the production of IL10 and TGF127 and generaized T cehyporesponsiveness128. In mice, CD25+ T

Regces restrain

the immunopathoogica response towards eggs duringschistosome infection129 and towards T. muris130 in thegut. Moreover, as mentioned above, depetion of CD25+T

Regces resuts in enhanced immunity to fiaria nema

todes in mice when combined with antibodies to GITRor CTLA4 (REFS 113,114).

FOXP3expressing TReg

ces may arise either directyfrom deveoping T ces in the thymus, or subsequentywhen naive periphera T ces are induced (for exampe,by TGF) to convert and express FOXP3. Expansionof both types of reguatory T ce popuation has beendemonstrated in heminth infections. In L. sigmodontisinfection, prior depetion of natura T

Regces reduces the

tota FOXP3+ TReg

ce response to infection and resutsin greater fiaria worm surviva5. However, we have asoshown that FOXP3 ovabuminspecific T ces are con

verted at a high rate to FOXP3+ ces in H. polygyrusinfected mice, and that this parasite reeases a productthat mimics mammaian TGF in driving the conversion of naive periphera T ces into suppressive FOXP3+T

Regces125. Other heminths adopt different poys; for

exampe, SEAs from S. mansoni do not directy induceT

Regces, but instead act on DCs to promote their induc

tion of FOXP3expressing CD4+ T ces131. Furthermore,T regulatory type 1 cells (T

R1 ces) are aso induced by

human DCs exposed to schistosomederived ysophosphatidyserine132 and show increased frequency in patent(microfiaraemic) fiariasis carriers133.

Other key immunoreguatory popuations demonstrate that the immune system has aso dupicated anddiversified its reguatory mechanisms. For exampe,reguatory B ces are active in patients with mutipescerosis whose remission is associated with heminthinfections134, and schistosomeinfected mice are pro

tected from anaphyactic shock135 and airway aergy136by an IL10producing B ce popuation. Moreover,H. polygyrusinfected mice generate reguatory B cesthat can, on transfer to naive hosts, downmoduate bothaergy and autoimmunity in a manner that is not IL10dependent137.

Innate effectors targeted by TH2type cytokines can

aso act as reguators. Aternativey activated macrophages are abe to bock infammatory proiferation ofymphocytes at the same time as mediating immunityto tissue heminths and repairing tissue that has beendamaged by parasites7,138. Eosinophis, the prototypicaT

H2type effector ce, produce TGF139 and promote

tissue remodeing140, exempifying the type 2 triad ofcounterinfammation, repair and parasite kiing. Suchmutitasking iustrates how the reguatory networkin vivo recruits nonprofessiona suppressive ces that areinfuenced by their signaing and cytokine environment.Equay, epitheia ces are major producers of TGF andIL10, particuary in the gut and airways.

The cost of immunity

A consistent feature of mammaian infection withmacropathogens is that compete expusion or kiing ofa parasites is rarey achieved141, presumaby because thecosts of achieving steriizing immunity exceed the benefits. These costs incude not ony the energy resources

of the immune response itsef but aso the damage associated with attempting to contain arge, often migratingparasites142. Indeed, immunopathoogy is frequenty theovert disease manifestation associated with heminthinfection, as T

H2type immune reactivity in excess is

not necessariy antiinfammatory. In mouse schistosomiasis, IL13mediated granuomatous infammationto eggs odged in the iver causes severe disease, mirroring ifethreatening human hepatospenic schistosomiasis143,144. In this case, pathoogy is restrained by IL10(REF. 145) and by a decoy receptor for IL13 (REF. 143),iustrating the fact that T

H2type responses can be

protective or pathoogica depending on the baance of

REVIEWS




9/14

type 2 cytokines produced. Pathoogy is not restricted tooverzeaous T

H2type responses but, as described above,

poor reguation can uneash proinfammatory TH1 and

TH17type immune responses, which are associated with

chronic pathoogy in fiariasis126 and schistosomiasis108.The soution for the host is to create a baance in

which the parasite is toerated, as ong as homeostasis can be maintained. Eucidating how this baance is

achieved is crucia for our understanding, not ony ofheminth infection, but of immune reguation in genera.Such toerance (in the physioogica sense) requires thatsefdamage is minimized, and T

Regces may be cru

cia for invoking specific immunoogica toerance, asdiscussed above. However, when damage does occur, amore physioogica toerance mechanism wi incude theabiity to repair the damage. Ecoogists eeganty describethis baance between resistance and toerance146, but inferthat these are opposing forces. In fact, T

H2type effector

pathways provide evidence that toerance, in the form ofimmune reguation, and wound repair can occur simutaneousy with antiparasite effector function. Type 2

immunity probaby evoved as a means to maintainhomeostasis in the face of macroparasite attack (FIG. 4),requiring both toerance and resistance mechanisms toachieve optima fitness.

The IL4RSTAT6 pathway ideay iustrates theconcept that toerance and resistance can be sequentiapoints in the same effector pathway. Receptor igationresuts in the production of characteristic aternativey

activated macrophage markers (namey, arginase 1,RELM, chitinase 3ike protein 3 and chitinase 3ikeprotein 4 (REFS 147,148)), which are aso produced bya range of other ces in response to IL4 and IL13(REF. 7). Arginase 1 provides the best exampe of a moecue contributing directy to reguation and woundrepair as we as to resistance to infection, as its activity generates proine, which is essentia for coagensynthesis, and poyamines for ce growth149. The substrate for arginase 1, larginine, is aso metaboized byinducibe nitric oxide synthase (iNOS; aso known asNOS2), which is expressed by IFN and LPSinducedcassicay activated macrophages. Thus, by competing

Figure 4 |Homeostasis and tolerance in helminth infections. Four interrelated states of tolerance are illustrated.

a | In immunosuppression, effector responses are negated by suppressive cytokines released from regulatory lymphocytes,

through mechanisms that are well characterized in diverse immunological systems. b | In immunological tolerance,

effector T helper 2 (TH2) cells enter a state of anergy and do not progress through to effector cells that would otherwise

mediate allergy, for example. The anergic state is marked by the expression of cytotoxic T lymphocyte antigen 4 (CTLA4)

and glucocorticoid-induced TNFR-related protein (GITR) and may be maintained by autocrine interleukin-10 (IL-10). c | In

physiological tolerance, innate cell populations participate in damage limitation and repair, so that the cost of infection is

minimized. d | In the modified TH2type response, the downstream effects of regulatory mechanisms are muted. Thisincludes switching antibody production to the noninflammatory isotype IgG4 (in humans), ablation of the eosinophil

response (for example in the allergic airway setting) and modulation of the granulomas that form around schistosome

eggs. DC, dendritic cell; RELM, resistin-like molecule-; TR1,T regulatory type 1; T

Reg, regulatory T.

REVIEWS




10/14

Hygiene hypothesis

This hypothesis originally

proposed that the increased

incidence of atopic diseases in

westernized countries was a

consequence of living in an

overly clean environment, with

reduced bacterial exposure

predisposing to increased

T helper 2 (TH2)-type allergic

responses to harmless

antigens. More recently, it has

been proposed that an

absence of exposure to a

broader range of pathogens,

including helminths, may

weaken the immunoregulatory

controls that exist to restrain

allergy and autoimmune

disease.

for the substrate required for nitric oxide production,arginase 1 is broady antiinfammatory. Arginase 1 isaso a potent suppressor of T ce activation owing to itsabiity to depete oca larginine, which is essentia forTce activation150. Athough in chronic heminth infection aternativey activated macrophagederived arginase 1 suppresses fibrosis through the negative reguationof T

H2 ces69, arginase 1 is required for H. polygyrus

expusion foowing chaenge of immune mice, possiby through ocaized deprivation of an essentia aminoacid28. Thus, arginase 1 contributes to parasite contro aswe as to immune reguation and tissue repair.

Simiar dichotomies exist for RELM; this moecuecontributes to tissue remodeing 151153, but RELMdeficient mice exhibit enhanced fibrosis becauseRELM can suppress T

H2 ces68,70. A protective func

tion for RELM has yet to be described during heminthinfection but its cose reative, RELM, has direct antinematode activity22. Both RELM and RELM areinduced by IL4R signaing and, with 49% aminoacid identity, have very simiar physica properties.

However, RELM is expressed in aternativey activated

macrophages throughout the body, as we as in bronchiaepitheium, whereas RELM is predominanty expressedin the gut epitheium23,40,68. It seems ikey that RELMwi aso be found to possess antiworm properties.Chitinase 3ike protein 3 is simiary impicated in theresponse to injury76,154 and immune reguation155,156, andits reationship to the chitinase famiy and its abundantsecretion by macrophages make it an exceent candidateantiworm effector moecue. The diversity of arginase 1,RELM and chitinase 3ike protein 3 functions maycorrespond to differences in context and in the specificcetype responding to IL4 or IL13, as discussed above.Overa, the picture is emerging in which the immunesystem is economica with its resources, using pathwaysthat are compatibe with both toerance and resistance and that can be taiored to minimize harm whiemaximizing parasite excusion and repair.

Coevolution of the immune response

It is a truism that the immune system coevoved withpathogens, even if its evoutionary origins are rooted

in ce recognition, tissue repair and the reguation ofcommensas157. Generay, this principe is conceptuaized in terms of a moecuar arms race between effectormechanisms and immune evasion strategies in whichreceptors, igands and signaing pathways are constantymatched and mismatched. However, a more quantitativeaspect shoud aso be considered that the intensity ofthe immune response has evoved in concert with theuniverse of pathogens. In particuar, the immune systemhas evoved in the constant presence of heminths, whieheminths have evoved to dampen, rather than disabe,the immune system of their hosts.

A quantitative evoutionary approach can ink thereduced incidence of immunopathoogica diseasesin heminthendemic nations with the identificationof genetic oci that increase the ikeihood of deveoping these diseases in Western countries158. Many of theaees at such oci reguate the extent and rate of theproduction of immunoogicay active proteins. In thisadaptation of the hygiene hypothesis (which originayposited that increased aergy resuted from diminishedbacteria stimuation), we woud argue that the immunesystem has evoved to operate optimay in the presence of heminth downmoduation, so that the eve ofimmune reactivity has been caibrated by evoution tocompensate for parasiteinduced dampening of immuneresponses, whie minimizing the risk of incurring ife

threatening heminthgenerated pathoogy from eitheruncontroed worm oads or overzeaous infammatoryreactions (shown in red in FIG. 5a). In contemporarysocieties without endemic heminth infections, proinfammatory aees that evoved to maintain immunefitness are now seen as responsibe for immunopathoogies in the human popuation (FIG. 5b). Heminths mayaso have driven diversification of immunoogica genes,as popuations from countries with high numbers ofdifferent heminth species show more extensive singenuceotide poymorphism (SNP) variation in 100 majorimmunoogica oci than popuations from historicayheminthsparse regions159.

Figure 5 | Evolution of immune responsiveness to

compensate for parasite immunosuppression. Thehuman population displays extensive polymorphism in

immune-related genes, many of which are non-coding

alleles that exert small quantitative rheostatlike effects

on the level of immune responsiveness. To evolve the

optimal level of responsiveness, alleles that compensate

for the mildly suppressive effect of parasites will have

been positively selected, with extremes of under or

over-responders relatively rare (a). In modern-day

environments, in the absence of parasite immune

modulation, more pro-inflammatory genotypes that

previously provided a high level of immune fitness may

now be associated with the development of pathological

allergy and autoimmunity (b).

REVIEWS




11/14

The immune moduation by heminths in humansand in aboratory rodents, discussed above, has recentybeen compemented by studies on wid mice (Apodemussylvaticus), in which H. polygyrusinfection downreguated tumour necrosis factor (TNF) responses to TLRstimuation160. Hence, the dampening of immunoreactivity by heminths is ikey to have been a significantfeature in the evoution of most extant mammaianspecies, and further investigations into the immunoogy of wid anima popuations may be very rewarding. Indeed, a recent study of Soay sheep showed that astrong immune response aows femae sheep to surviveharsh winters, during which high nematode burdensare the major determinant of death, but at the cost ofreduced reproductive success that was associated withsefreactive antibodies161. Such fitness tradeoffs maymaintain the observed genetic variation in immuneresponsiveness.

The host and the parasite: a continuing dialogue

Once TH

2type immune responses are initiated by

the presence of a heminth, the diaogue is not justbetween ces of the immune system the parasitesthemseves activey contribute to the conversation. Asdiscussed above, heminth parasites induce mutipeimmunosuppressive mechanisms in the host (incudingreguatory T and B ces), through the use of moecuar pairing between parasite igands and host receptors(such as the binding ofH. polygyrus secreted productsto TGF receptors). Perhaps ess we appreciated ishow heminths themseves specificay respond to theirimmunoogica environment. In both human infectionand mouse modes, S. mansoni appear to require hostT ces for norma worm deveopment and transmission162164. In a different scenario, fiaria arvae deveopnormay in the absence of host immune responses butacceerate their deveopment and produce offspringsooner in the presence of eosinophis, the host ce mostresponsibe for arva destruction165. A simiar dependence on host eosinophis has aso been reported forTrichinella spiralis infections in mice166.This suggests

that worms are abe to adjust their deveopmenta schedue to maximize fitness in the immune environment ofa particuar host.

Cruciay, the diaogue is not just between the hostand a singe parasite but wi normay incude additiona parasites (both microorganisms and metazoans), which compete with the host and each other forresources. This threeway (or manyway) dynamic hasthe capacity to dramaticay ater patterns of host susceptibiity and resistance167. In the intestina setting, weincreasingy appreciate that these interactions incudethe commensa fora. As microbia composition canaffect systemic responses, in terms of both T

Hce subset

deveopment and specific responsiveness to a particuarantigen chaenge, more attention wi need to be paidto how heminths interact with bacteria cohabitantsand whether they manipuate the microbia popuationfor their own ends. An eary insight into this excitingarea has recenty been provided by the observation that,on entering the intestine, T. muris eggs deay the pointof hatching unti they detect the presence of coonic

bacteria168, thus ensuring that the arvae emerge into themost favourabe environment.

Conclusions

The mutipicity of type 2 components that respond toheminths continues to expand with the discovery notony of new ce types, but of increasing overap, paraeism and interdependence between ces and their moecuar mediators. To understand this compexity, we needto move away from paradigms based on enzyme andsignaing cascades and see the type 2 response as akin toa neura network, with a web of interactions and aternative pathways from which activated ce popuations canintegrate information to seect and caibrate their outputappropriatey. A better appreciation of these circuits wipave the way to understanding heminths and how ourresponse to them has evoved, as we as how to achieveeffective immunity in the absence of pathoogy and, morebroady, how best to moduate the immune system inaergy, autoimmunity and cancer.

1. Koyasu, S., Moro, K., Tanabe, M. & Takeuchi, T.

Natural helper cells: a new player in the innate

immune response against helminth infection.

Adv. Immunol.108, 2144 (2010).

2. Saenz, S. A., Noti, M. & Artis, D. Innate immune cell

populations function as initiators and effectors in Th2

cytokine responses. Trends Immunol.31, 407413

(2010).

3. Wojciechowski, W. et al. Cytokineproducing effectorB cells regulate type 2 immunity to H. polygyrus.

Immunity30, 421433 (2009).

4. Paul, W. E. & Zhu, J. How are TH2type immune

responses initiated and amplified? Nature Rev.

Immunol.10, 225235 (2010).

5. Taylor, M. D. et al. Early recruitment of natural CD4+

Foxp3+ Treg cells by infective larvae determines the

outcome of filarial infection. Eur. J. Immunol.39,

192206 (2009).

6. Finkelman, F. D. et al. Interleukin4 and interleukin13

mediated host protection against intestinal nematode

parasites. Immunol. Rev.201, 139155 (2004).

7. Jenkins, S. J. & Allen, J. E. Similarity and diversity in

macrophage activation by nematodes, trematodes,

and cestodes.J. Biomed. Biotechnol.2010, 262609

(2010).

8. Anthony, R. M., Rutitzky, L. I., Urban, J. F.,

Stadecker, M. J. & Gause, W. C. Protective immune

mechanisms in helminth infection. Nature Rev.

Immunol.7, 975987 (2007).

9. Neill, D. R. & McKenzie, A. N. J. Nuocytes and

beyond: new insights into helminth expulsion.

Trends Parasitol.27, 214221 (2011).

10. Vignali, D. A. et al. A role for CD4+ but not CD8+

T cells in immunity to Schistosoma mansoniinduced

by 20 kradirradiated and Ro 113128terminated

infections. Immunology67, 466472 (1989).11. Katona, I. M., Urban, J. F. & Finkelman, F. D.

The role of L3T4+ and Lyt2+ T cells in the IgE response

and immunity to Nippostrongylus brasiliensis.

J. Immunol.140, 32063211 (1988).12. Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R. M.

Analysis of type 2 immunity in vivo with a bicistronic

IL4 reporter. Immunity15, 303311 (2001).

This study developed and used a powerful method

for tracking IL4producing cells.

13. Urban, J. F. et al. IL13, IL4R, and Stat6 are

required for the expulsion of the gastrointestinal

nematode parasite Nippostrongylus brasiliensis.

Immunity8, 255264 (1998).

14. Zhu, J. et al. Conditional deletion of Gata3 shows its

essential function in TH1T

H2 responses. Nature

Immunol.5, 11571165 (2004).

15. Voehringer, D., Reese, T. A., Huang, X., Shinkai, K. &

Locksley, R. M. Type 2 immunity is controlled by

IL4/IL13 expression in hematopoietic noneosinophil

cells of the innate immune system.J. Exp. Med.203,

14351446 (2006).

16. Neill, D. R. et al. Nuocytes represent a new innate

effector leukocyte that mediates type2 immunity.

Nature464, 13671370 (2010).17. Moro, K. et al. Innate production of T

H2 cytokines by

adipose tissueassociated cKit+Sca1+ lymphoid cells.

Nature463, 540544 (2010).18. Price, A. E. et al. Systemically dispersed innate

IL13expressing cells in type 2 immunity. Proc. Natl

Acad. Sci. USA107, 1148911494 (2010).

19. Saenz, S. A. et al. IL25 elicits a multipotent

progenitor cell population that promotes TH2

cytokine responses. Nature464, 13621366

(2010).

References 1619 defined the phenotype and

functional role of innate helper cells in

gastrointestinal nematode infection.

20. Saenz, S. A., Taylor, B. C. & Artis, D. Welcome to

the neighborhood: epithelial cellderived cytokines

license innate and adaptive immune responses at

mucosal sites. Immunol. Rev.226, 172190

(2008).

21. Hasnain, S. Z. et al. Muc5ac: a critical component

mediating the rejection of enteric nematodes.

J.Exp.Med.208, 893900 (2011).

REVIEWS




12/14

22. Herbert, D. R. et al. Intestinal epithelial cell secretion

of RELM protects against gastrointestinal worm

infection.J. Exp. Med.206, 29472957 (2009).

This study demonstrates that an innate epithelial

cell product exerts direct antiparasite effects on

gut nematodes.23. Artis, D. et al. RELM/FIZZ2 is a goblet cellspecific

immuneeffector molecule in the gastrointestinal tract.

Proc. Natl Acad. Sci. USA101, 1359613600 (2004).

24. Akiho, H., Blennerhassett, P., Deng, Y. & Collins, S. M.

Role of IL4, IL13, and STAT6 in inflammation

induced hypercontractility of murine smooth musclecells.Am. J. Physiol. Gastrointest. Liver Physiol.282,

G226G232 (2002).

25. Cliffe, L. J. et al. Accelerated intestinal epithelial cell

turnover: a new mechanism of parasite expulsion.

Science308, 14631465 (2005).

The discovery of an important new TH2 cell

mediated mechanism of protection against

parasites in the GI tract.26. McDermott, J. R. et al. Mast cells disrupt epithelial

barrier function during enteric nematode infection.

Proc. Natl Acad. Sci. USA100, 77617766 (2003).

27. Sasaki, Y. et al. IL18 with IL2 protects against

Strongyloides venezuelensis infection by activating

mucosal mast celldependent type 2 innate immunity.

J. Exp. Med.202, 607616 (2005).28. Anthony, R. M.et al. Memory T

H2 cells induce

alternatively activated macrophages to mediate

protection against nematode parasites. Nature Med.

12, 955960 (2006).

The first description of an antiparasite role for

alternatively activated macrophages.

29. Min, B. et al. Basophils produce IL4 and accumulate

in tissues after infection with a Th2inducing parasite.

J. Exp. Med.200, 507517 (2004).

30. Mitre, E., Taylor, R. T., Kubofcik, J. & Nutman, T. B.

Parasite antigendriven basophils are a major source

of IL4 in human filarial infections.J. Immunol.172,

24392445 (2004).

31. Karasuyama, H., Wada, T., Yoshikawa, S. & Obata, K.

Emerging roles of basophils in protective immunity

against parasites. Trends Immunol.32, 125130

(2011).32. Ohnmacht, C. et al. Basophils orchestrate chronic

allergic dermatitis and protective immunity against

helminths. Immunity33, 364374 (2010).

This study defines the roles, and the boundaries,

of basophils during tissue and gut nematode

infection.

33. Kim, S. et al. Basophils are transiently recruited into

the draining lymph nodes during helminth infection

via IL3, but infectioninduced Th2 immunity candevelop without basophil lymph node recruitment or

IL3.J. Immunol.184, 11431147 (2010).

34. Sabin, E. A., Kopf, M. A. & Pearce, E. J. Schistosoma

mansoniegginduced early IL4 production is

dependent upon IL5 and eosinophils.J. Exp. Med.

184, 18711878 (1996).

35. Knott, M. L. et al. Impaired resistance in early

secondary Nippostrongylus brasiliensis infections

in mice with defective eosinophilopoeisis.

Int. J. Parasitol.37, 13671378 (2007).

36. Spencer, L. A. & Weller, P. F. Eosinophils and Th2

immunity: contemporary insights. Immunol. Cell Biol.

88, 250256 (2010).

37. Padigel, U. M. et al. Signaling through Gi2 protein isrequired for recruitment of neutrophils for antibody

mediated elimination of larval Strongyloides

stercoralis in mice.J. Leukoc. Biol.81, 11201126

(2007).

38. AlQaoud, K. M. et al. A new mechanism for

IL5dependent helminth control: neutrophilaccumulation and neutrophilmediated worm

encapsulation in murine filariasis are abolished in the

absence of IL5. Int. Immunol.12, 899908 (2000).

39. Harvie, M. et al. The lung is an important site for

priming CD4 Tcellmediated protective immunity

against gastrointestinal helminth parasites. Infect.

Immun.78, 37533762 (2010).

40. Nair, M. G. et al. Chitinase and Fizz family members

are a generalized feature of nematode infection with

selective upregulation of Ym1 and Fizz1 by antigen

presenting cells. Infect. Immun.73, 385394 (2005).

41. Reece, J. J., Siracusa, M. C. & Scott, A. L. Innate

immune responses to lungstage helminth infection

induce alternatively activated alveolar macrophages.

Infect. Immun.74, 49704981 (2006).

42. Satoguina, J. S., Weyand, E., Larbi, J. & Hoerauf, A.

T regulatory1 cells induce IgG4 production by B cells:

role of IL10.J. Immunol.174, 47184726 (2005).

43. Harris, N. & Gause, W. C. To B or not to B: B cells

and the Th2type immune response to helminths.

Trends Immunol.32, 8088 (2011).

44. McCoy, K. D. et al. Polyclonal and specific antibodies

mediate protective immunity against enteric helminth

infection. Cell Host Microbe4, 362373 (2008).

This study defines the settings in which antibodies

function in an antinematode role, including the

importance of polyclonal immunoglobulins.

45. Dunne, D. W. et al. Immunity after treatment of

human schistosomiasis: association between IgE

antibodies to adult worm antigens and resistance toreinfection. Eur. J. Immunol.22, 14831494 (1992).46. Kooyman, F. et al. Protection in lambs vaccinated with

Haemonchus contortus antigens is age related, and

correlates with IgE rather than IgG1 antibody.

Parasite Immunol.22, 1320 (2000).

47. de Andres, B. et al. Lack of Fc receptors on murineeosinophils: implications for the functional significance

of elevated IgE and eosinophils in parasitic infections.

Blood89, 38263836 (1997).

48. Capron, M. & Capron, A. Immunoglobulin E and

effector cells in schistosomiasis. Science264,

18761877 (1994).

49. Abraham, D. et al. Immunoglobulin E and eosinophil

dependent protective immunity to larval Onchocerca

volvulus in mice immunized with irradiated larvae.

Infect. Immun.72, 810817 (2004).

50. Maizels, R. M. & Yazdanbakhsh, M. Immune

regulation by helminth parasites: cellular and

molecular mechanisms. Nature Rev. Immunol.3,

733744 (2003).

51. PlattsMills, T. A. E., Woodfolk, J. A., Erwin, E. A. &

Aalberse, R. Mechanisms of tolerance to inhalant

allergens: the relevance of a modified Th2 response to

allergens from domestic animals. Springer Semin.

Immunopathol.25, 271279 (2004).52. RodrguezSosa, M. et al. A STAT4dependent Th1

response is required for resistance to the helminth

parasite Taenia crassiceps.Infect. Immun.72,

45524560 (2004).

53. Wynn, T. A. et al. IL12 enhances vaccineinduced

immunity to schistosomes by augmenting both

humoral and cellmediated immune responses

against the parasite.J. Immunol.157, 40684078

(1996).

54. Dessein, A. et al. Interleukin13 in the skin and

interferon in the liver are key players in immune

protection in human schistosomiasis. Immunol. Rev.

201, 180190 (2004).

55. Daz, A. & Allen, J. E. Mapping immune response

profiles: the emerging scenario from helminth

immunology. Eur. J. Immunol.37, 33193326(2007).

56. James, S. L. & Glaven, J. Macrophage cytotoxicity

against schistosomula ofSchistosoma mansoni

involves argininedependent production of reactive

nitrogen intermediates.J. Immunol.143, 42084212

(1989).

57. Allen, J. E. & Wynn, T. A. Evolution of Th2 immunity:

a rapid repair response to the tissue destructive

pathogens. PLoS Pathog.7, e1002003 (2011).

58. Miyake, K., Tanaka, T. & McNeil, P. L. Disruption

induced mucus secretion: repair and protection.

PLoS Biol.4, e276 (2006).

59. Enoksson, M. et al. Mast cells as sensors of cell injury

through IL33 recognition.J. Immunol. 186,

25232528 (2011).60. Lee, J. J., Jacobsen, E. A., McGarry, M. P.,

Schleimer, R. P. & Lee, N. A. Eosinophils in health and

disease: the LIAR hypothesis. Clin. Exp. Allergy40,

563575 (2010).

61. Eming, S. A., Krieg, T. & Davidson, J. M. Inflammationin wound repair: molecular and cellular mechanisms.

J. Invest. Dermatol.127, 514525 (2007).62. Redente, E. F.et al. Differential polarization of alveolar

macrophages and bone marrowderived monocytes

following chemically and pathogeninduced chronic

lung inflammation.J. Leukoc. Biol.88, 159168

(2010).

63. Profet, M. The function of allergy: immunological

defense against toxins. Q. Rev. Biol.66, 2362

(1991).

64. Skugor, S., Glover, K. A., Nilsen, F. & Krasnov, A.

Local and systemic gene expression responses of

Atlantic salmon (Salmo salarL.) to infection with

the salmon louse (Lepeophtheirus salmonis).

BMC Genomics9, 498 (2008).

65. Seno, H. et al. Efficient colonic mucosal wound repair

requires Trem2 signaling. Proc. Natl Acad. Sci. USA

106, 256261 (2009).

66. Turnbull, I. R. et al. Cutting edge: TREM2 attenuates

macrophage activation.J. Immunol.177,

35203524 (2006).

67. Khn, H. & ODonnell, V. B. Inflammation and immune

regulation by 12/15lipoxygenases. Prog. Lipid Res.

45, 334356 (2006).68. Nair, M. G. et al. Alternatively activated macrophage

derived RELM is a negative regulator of type 2

inflammation in the lung.J. Exp. Med.206, 937952

(2009).

69. Pesce, J. T. et al. Arginase1expressing macrophages

suppress Th2 cytokinedriven inflammation andfibrosis. PLoS Pathog.5, e1000371 (2009).

This study provides evidence that arginase 1,

a TH2type effector molecule, may have different

functions depending on the cell type that produces it.

70. Pesce, J. T. et al. Retnla (Relm/Fizz1) suppresses

helminthinduced Th2type immunity. PLoS Pathog.

5, e1000393 (2009).

71. Edwards, A. D. et al. Microbial recognition via Tolllike

receptordependent and independent pathways

determines the cytokine response of murine dendritic

cell subsets to CD40 triggering.J. Immunol.169,

36523660 (2002).

72. Robinson, M. J. et al. Dectin2 is a Sykcoupled

pattern recognition receptor crucial for Th17

responses to fungal infection.J. Exp. Med.206,

20372051 (2009).

73. Balic, A., Harcus, Y., Holland, M. J. & Maizels, R. M.

Selective maturation of dendritic cells by

Nippostrongylus brasiliensissecreted proteins drives

Th2 immune responses. Eur. J. Immunol.34,

30473059 (2004).

74. Cervi, L., MacDonald, A. S., Kane, C., Dzierszinski, F.

& Pearce, E. J. Dendritic cells copulsed with

microbial and helminth antigens undergo modified

maturation, segregate the antigens to distinct

intracellular compartments, and concurrently

induce microbespecific Th1 and helminthspecific

Th2 responses.J. Immunol.172, 20162020

(2004).

75. Robinson, M. W., Hutchinson, A. T., Donnelly, S. &

Dalton, J. P. Worm secretory molecules are causing

alarm. Trends Parasitol .26, 371372 (2010).76. Loke, P. et al. Alternative activation is an innate

response to injury that requires CD4+ T cells to be

sustained during chronic infection.J. Immunol.179,

39263936 (2007).

This paper reports that IL4Rresponses are an

innate response to injury and has implications for

TH2type immunity and wound repair.

77. Zhao, A. et al. Critical role of IL25 in nematode

infectioninduced alterations in intestinal function.J. Immunol.185, 69216929 (2010).

78. Kouzaki, H., OGrady, S. M., Lawrence, C. B. & Kita, H.

Proteases induce production of thymic stromal

lymphopoietin by airway epithelial cells through

proteaseactivated receptor2.J. Immunol. 183,

14271434 (2009).

79. Lthi, A. U. et al. Suppression of interleukin33

bioactivity through proteolysis by apoptotic caspases.

Immunity31, 8498 (2009).

80. Tawill, S., Le Goff, L., Ali, F., Blaxter, M. & Allen, J. E.

Both freeliving and parasitic nematodes induce a

characteristic Th2 response that is dependent on

the presence of intact glycans. Infect. Immun.72,

398407 (2004).

81. Everts, B. et al. Omega1, a glycoprotein secreted by

Schistosoma mansonieggs, drives Th2 responses.

J. Exp. Med.206, 16731680 (2009).

82. Hewitson, J. P., Grainger, J. R. & Maizels, R. M.

Helminth immunoregulation: the role of parasite

secreted proteins in modulating host immunity.Mol. Biochem. Parasitol.167, 111 (2009).

83. Jankovic, D. et al. In the absence of IL12, CD4+

T cell responses to intracellular pathogens fail to

default to a Th2 pattern and are host protective in

an IL10/ setting. Immunity16, 429439 (2002).

84. Steinfelder, S. et al. The major component in

schistosome eggs responsible for conditioning

dendritic cells for Th2 polarization is a T2

ribonuclease (omega1).J. Exp. Med.206,

16811690 (2009).

Together with reference 81, this study identifies an

individual TH2type responsedriving molecule from

schistosome eggs that acts via DCs.85. van Liempt, E. et al.Schistosoma mansonisoluble

egg antigens are internalized by human dendritic cells

through multiple Ctype lectins and suppress TLR

induced dendritic cell activation. Mol. Immunol.44,

26052615 (2007).

REVIEWS




13/14

86. Ritter, M. et al.Schistosoma mansonitriggers

Dectin2, which activates the Nlrp3 inflammasome

and alters adaptive immune responses. Proc. Natl

Acad. Sci. USA107, 2045920464 (2010).

87. Perrigoue, J. G. et al. MHC class IIdependent

basophilCD4+ T cell interactions promote TH2

cytokinedependent immunity. Nature Immunol.10,

697705 (2009).

88. PhythianAdams, A. T. et al. CD11c depletion severely

disrupts Th2 induction and development in vivo.

J. Exp. Med. 207, 20892096 (2010).

89. MacDonald, A. S. & Pearce, E. J. Cutting edge:polarized Th cell response induction by transferred

antigenpulsed dendritic cells is dependent on IL4 or

IL12 production by recipient cells.J. Immunol.168,

31273130 (2002).

90. Torrero, M. N. , Hbner, M. P., Larson, D.,

Karasuyama, H. & Mitre, E. Basophils amplify type 2

immune responses, but do not serve a protective role,

during chronic infection of mice with the filarial

nematode Litomosoides sigmodontis.J. Immunol.

185, 74267434 (2010).

91. Everts, B., Smits, H. H., Hokke, C. H. &

Yazdanbakhsh, M. Helminths and dendritic cells:

sensing and regulating via pattern recognition

receptors, Th2 and Treg responses. Eur. J. Immunol.

40, 15251537 (2010).

92. MacDonald, A. S. & Maizels, R. M. Alarming dendritic

cells for Th2 induction.J. Exp. Med.205, 1317

(2008).93. Horsnell, W. G. C. et al. Delayed goblet cell

hyperplasia, acetylcholine receptor expression, and

worm expulsion in SMCspecific IL4Rdeficient mice.

PLoS Pathog.3, e1 (2007).

94. Taylor, B. C. et al. TSLP regulates intestinal immunity

and inflammation in mouse models of helminth

infection and colitis.J. Exp. Med.206, 655667

(2009).

95. Massacand, J. C. et al. Helminth products bypass the

need for TSLP in Th2 immune responses by directly

modulating dendritic cell function. Proc. Natl Acad.

Sci. USA106, 1396813973 (2009).

96. Segura, M., Su, Z., Piccirillo, C. & Stevenson, M. M.

Impairment of dendritic cell function by excretory

secretory products: a potential mechanism for

nematodeinduced immunosuppression.

Eur. J. Immunol.37, 18871904 (2007).97. Mylonas, K. J., Nair, M. G., PrietoLafuente, L.,

Paape, D. & Allen, J. E. Alternatively activated

macrophages elicited by helminth infection can

be reprogrammed to enable microbial killing.

J. Immunol. 182, 30843094 (2009).

98. Loke, P., MacDonald, A. S. & Allen, J. E. Antigenpresenting cells recruited by Brugia malayiinduce

Th2 differentiation of nave CD4+ T cells.

Eur. J. Immunol.30, 11271135 (2000).

99. Huber, S., Hoffmann, R., Muskens, F. & Voehringer, D.

Alternatively activated macrophages inhibit Tcell

proliferation by Stat6dependent expression of PDL2.

Blood116, 33113320 (2010).

100. Terrazas, L. I., Montero, D., Terrazas, C. A., Reyes, J. L.

& RodrguezSosa, M. Role of the programmed

Death1 pathway in the suppressive activity of

alternatively activated macrophages in experimental

cysticercosis. Int. J. Parasitol.35, 13491358

(2005).

101. Munder, M. et al. Arginase I is constitutively

expressed in human granulocytes and participates in

fungicidal activity. Blood105, 25492556 (2005).

102. Babu, S., Kumaraswami, V. & Nutman, T. B.

Alternatively activated and immunoregulatory

monocytes in human filarial infections.J. Infect. Dis.

199, 18271837 (2009).103. Zaretsky, A. G. et al. T follicular helper cells

differentiate from Th2 cells in response to helminth

antigens.J. Exp. Med.206, 991999 (2009).

104.Veldhoen, M. et al. Transforming growth factor

reprograms the differentiation of T helper 2 cells

and promotes an interleukin 9producing subset.

Nature Immunol.9, 13411346 (2008).

105. Zhou, L., Chong, M. M. W. & Littman, D. R.

Plasticity of CD4+ T cell lineage differentiation.

Immunity30, 646655 (2009).

106. Balic, A., Harcus, Y. M., Taylor, M. D., Brombacher, F.

& Maizels, R. M. IL4R signaling is required to induce

IL10 for the establishment of Th2 dominance.

Int. Immunol.18, 14211431 (2006).

107. Helmby, H. & Grencis, R. K. Contrasting roles for IL10

in protective immunity to different life cycle stages of

intestinal nematode parasites. Eur. J. Immunol.33,

23822390 (2003).

108. Rutitzky, L. I. et al. IL23 is required for the

development of severe egginduced immunopathology

in schistosomiasis and for lesional expression of IL17.

J. Immunol.180, 24862495 (2008).

109. PedrasVasconcelos, J. A. & Pearce, E. J. Type 1 CD8+

T cell responses during infection with the helminth

Schistosoma mansoni.J. Immunol.157, 30463053

(1996).

110. Mallevaey, T. et al. Activation of invariant NKT cells by

the helminth parasite Schistosoma mansoni.

J. Immunol.176, 24762485 (2006).

111. Boros, D. L., Pelley, R. P. & Warren, K. S.Spontaneous modulation of granulomatous

hypersensitivity in schistosomiasis mansoni.

J. Immunol.114, 14371441 (1975).

112. Sartono, E., Kruize, Y. C., Kurniawan, A., Maizels, R. M.

& Yazdanbakhsh, M. Depression of antigenspecific

interleukin5 and interferon responses in human

lymphatic filariasis as a function of clinical status and

age.J. Infect. Dis.175, 12761280 (1997).

113. Taylor, M. D. et al. Removal of regulatory T cell

activity reverses hyporesponsiveness and leads to

filarial parasite clearance in vivo.J. Immunol.174,

49244933 (2005).

This was the first description of the requirement

for TReg

cells to maintain susceptibility to nematode

infection.114. Taylor, M. D. et al. CTLA4 and CD4+ CD25+

regulatory T cells inhibit protective immunity to filarial

parasites in vivo.J. Immunol.179, 46264634

(2007).

115. Grogan, J. L., Kremsner, P. G., Deelder, A. M. &

Yazdanbakhsh, M. Antigenspecific proliferation and

interferon and interleukin5 production are down

regulated during Schistosoma haematobium infection.

J. Infect. Dis.177, 14331437 (1998).

116. Taylor, J. J., Krawczyk, C. M., Mohrs, M. & Pearce, E. J.

Th2 cell hyporesponsiveness during chronic murine

schistosomiasis is cell intrinsic and linked to GRAIL

expression.J. Clin. Invest.119, 10191028 (2009).

117. Smith, P. et al.Schistosoma mansoniworms induce

anergy of T cells via selective upregulation of

programmed death ligand 1 on macrophages.

J. Immunol.173, 12401248 (2004).118. Finney, C. A. M., Taylor, M. D., Wilson, M. S. &

Maizels, R. M. Expansion and activation of

CD4+CD25+ regulatory T cells in Heligmosomoides

polygyrus infection. Eur. J. Immunol.37, 18741886

(2007).

119. Rausch, S. et al. Functional analysis of effector and

regulatory T cells in a parasitic nematode infection.

Infect. Immun.76, 19081919 (2008).

120. Fleming, J. & Fabry, Z. The hygiene hypothesis andmultiple sclerosis.Ann. Neurol.61, 8589 (2007).

121. Elliott, D. E., Summers, R. W. & Weinstock, J. V.

Helminths as governors of immunemediated

inflammation. Int. J. Parasitol.37, 457464 (2007).

122. Maizels, R. M. Infections and allergy helminths,

hygiene and host immune regulation. Curr. Opin.

Immunol.17, 656661 (2005).

123. Fallon, P. G. & Mangan, N. E. Suppression of TH2type

allergic reactions by helminth infection. Nature Rev.

Immunol.7, 220230 (2007).

124. McSorley, H. J., Harcus, Y. M., Murray, J., Taylor, M. D.

& Maizels, R. M. Expansion of Foxp3+ regulatory

T cells in mice infected with the filarial parasite

Brugia malayi.J. Immunol.181, 64566466 (2008).

125. Grainger, J. R. et al. Helminth secretions induce

de novo T cell Foxp3 expression and regulatory

function through the TGF pathway.J. Exp. Med.207, 23312341 (2010).

This study demonstrates that expansion of TReg

cell

populations in helminth infection can be driven byparasite products exploiting the TGF pathway.

126. Babu, S. et al. Filarial lymphedema is characterized

by antigenspecific Th1 and Th17 proinflammatory

responses and a lack of regulatory T cells.

PLoS Negl. Trop. Dis.3, e420 (2009).

127. Turner, J. D. et al. Intensity of intestinal infection

with multiple worm species is related to regulatory

cytokine output and immune hyporesponsiveness.

J. Infect. Dis.197, 12041212 (2008).128. Figueiredo, C. A. et al. Chronic intestinal helminth

infections are associated with immune

hyporesponsiveness and induction of a regulatory

network. Infect. Immun.78, 31603167 (2010).

129. Layland, L. E., Rad, R., Wagner, H. & da Costa, C. U. P.

Immunopathology in schistosomiasis is controlled by

antigenspecific regulatory T cells primed in the

presence of TLR2. Eur. J. Immunol.37, 21742184

(2007).

130. DElia, R., Behnke, J. M., Bradley, J. E. & Else, K. J.

Regulatory T cells: a role in the control of helminth

driven intestinal pathology and worm survival.

J. Immunol.182, 23402348 (2009).

131. Zaccone, P. et al.Schistosoma mansoniegg antigens

induce Treg that participate in diabetes prevention

in NOD mice. Eur. J. Immunol.39, 10981107

(2009).

132. van der Kleij, D. et al. A novel hostparasite lipid

crosstalk. Schistosomal lysophosphatidylserine

activates Tolllike receptor 2 and affects immune

polarization.J. Biol. Chem.277, 4812248129(2002).133. Metenou, S. et al. At homeostasis filarial infections

have expanded adaptive T regulatory but not

classical Th2 cells. J. Immunol. 184, 53755382

(2010).

134. Correale, J., Farez, M. & Razzitte, G. Helminth

infections associated with multiple sclerosis induce

regulatory B cells.Ann. Neurol.64, 187199

(2008).

135. Mangan, N. E. et al. Helminth infection protects mice

from anaphylaxis via IL10producing B cells.

J. Immunol.173, 63466356 (2004).

136. Smits, H. H. et al. Protective effect ofSchistosoma

mansoniinfection on allergic airway inflammation

depends on the intensity and chronicity of infection.

J. Allergy Clin. Immunol.120, 932940 (2007).

137. Wilson, M. S. et al. Helminthinduced CD19+CD23hi

B cells modulate experimental allergic and

autoimmune inflammation. Eur. J. Immunol.40,

16821696 (2010).

138. Kreider, T., Anthony, R. M., Urban, J. F. & Gause, W. C.

Alternatively activated macrophages in helminth

infections. Curr. Opin. Immunol.19, 448453

(2007).

139. Wong, D. T. et al. Eosinophils from patients with blood

eosinophilia express transforming growth factor1.

Blood78, 27022707 (1991).

140. Humbles, A. A. et al. A critical role for eosinophils

in allergic airways remodeling. Science305,

17761779 (2004).

141. Behnke, J. M., Barnard, C. J. & Wakelin, D.

Understanding chronic nematode infections:

evolutionary considerations, current hypotheses and

the way forward. Int. J. Parasitol.22, 861907

(1992).142. Graham, A. L., Allen, J. E. & Read, A. F. Evolutionary

causes and consequences of immunopathology.

Annu. Rev. Ecol. Evol. Syst.36, 373397 (2005).

143. MentinkKane, M. M. & Wynn, T. A. Opposing roles

for IL13 and IL13 receptor 2 in health and disease.

Immunol. Rev.202, 191202 (2004).144. Hoffmann, K. F., Wynn, T. A. & Dunne, D. W.

Cytokinemediated host responses during

schistosome infections; walking the fine line between

immunological control and immunopathology.

Adv. Parasitol.52, 265307 (2002).

145. Hoffmann, K. F., James, S. L., Cheever, A. W. &

Wynn, T. A. Studies with double cytokinedeficient

mice reveal that highly polarized Th1 and Th2type

cytokine and antibody responses contribute equally to

vaccineinduced immunity to Schistosoma mansoni.

J. Immunol.163, 927938 (1999).

146. Schneider, D. S. & Ayres, J. S. Two ways to survive

infection: what resistance and tolerance can teach us

about treating infectious diseases. Nature Rev.

Immunol.8, 889895 (2008).147. Loke, P. et al. IL4 dependent alternativelyactivated

macrophages have a distinctive in vivo gene

expression phenotype. BMC Immunol.3, 7 (2002).148. Gordon, S. Alternative activation of macrophages.

Nature Rev. Immunol.3, 2335 (2003).149. Hesse, M. et al. Differential regulation of nitric oxide

synthase2 and arginase1 by type 1/type 2 cytokines

in vivo: granulomatous pathology is shaped by the

pattern of Larginine metabolism.J. Immunol.167,

65336544 (2001).150. Choi, B. et al. Differential impact of Larginine

deprivation on the activation and effector functions

of T cells and macrophages.J. Leukoc. Biol.85,

268277 (2009).

151. Teng, X., Li, D., Champion, H. C. & Johns, R. A.

FIZZ1/RELM, a novel hypoxiainduced mitogenic

factor in lung with vasoconstrictive and angiogenic

properties. Circ. Res. 92, 10651067 (2003).

152.YamajiKegan, K. et al. Hypoxiainduced mitogenic

factor (HIMF/FIZZ1/RELM) increases lung

inflammation and activates pulmonary microvascular

endothelial cells via an IL4dependent mechanism.

J. Immunol.185, 55395548 (2010).

REVIEWS




14/14

153. Liu, T. et al. FIZZ1 stimulation of myofibroblast

differentiation.Am. J. Pathol.164, 13151326

(2004).

154. Hung, S., Chang, A. C., Kato, I. & Chang, N. A.

Transient expression of Ym1, a heparinbinding

lectin, during developmental hematopoiesis and

inflammation.J. Leukoc. Biol.72, 7282 (2002).

155.Arora, M. et al. Simvastatin promotes Th2type

responses through the induction of the chitinase

family member Ym1 in dendritic cells. Proc. Natl Acad.

Sci. USA103, 77777782 (2006).

156. Cai, Y., Kumar, R. K., Zhou, J., Foster, P. S. &Webb, D. C. Ym1/2 promotes Th2 cytokine expression

by inhibiting 12/15(S)lipoxygenase: identification of a

novel pathway for regulating allergic inflammation.

J. Immunol.182, 53935399 (2009).

157. Weaver, C. T. & Hatton, R. D. Interplay between the

TH17 and T

Regcell lineages: a (co)evolutionary

perspective. Nature Rev. Immunol.9, 883889 (2009).

158. Maizels, R. M. Parasite immunomodulation and

polymorphisms of the immune system.J. Biol.8, 62

(2009).

159. Fumagalli, M. et al. Parasites represent a major

selective force for interleukin genes and shape the

genetic predisposition to autoimmune conditions.

J. Exp. Med. 206, 13951408 (2009).

This study provides evidence that populations

exposed to a greater ra

diversity and dialogue in immunity to helminths

Documents