innate responses of b cells

Mini-Review:

Innate responses of B cells

David Gray1, Mohini Gray2 and Tom Barr1

1 Institute of Immunology and Infection Research, University of Edinburgh, AshworthLabs, Edinburgh, UK

2 MRC Centre for Inflammation Research, The Queen's Medical Research Institute,University of Edinburgh, Edinburgh, UK

In this review, we describe the non-antibody-mediated functions of B cells within theimmune system. In addition to antibody production, B cells also present antigen toTcells, programme Tcell differentiation and regulate effector Tcell responses and muchof this is mediated by the cytokines they make. We focus on the potential of B cells toperform these functions simply as a result of activation via 'innate' receptors (e.g. Toll-like receptors) and often independently of BCR ligation. We feel an appreciation ofthese broad and often antigen-nonspecific functions is important at a time when there isan increasing use of B cell depletion as a therapy for autoimmune disease.

Introduction

B cells are best known as antibody producing cells.Antibodies are a first line defence against infection andmost vaccines work because they elicit a protectiveantibody response. However, there is darker side toantibody production if the B cells have a BCR specificitythat reacts with components of self. The autoantibodiesthey make can then precipitate the panoply ofinflammatory responses leading to the whole range ofautoimmune diseases. It is perhaps not surprising,therefore, that clinicians wishing to alleviate symptomsand possibly treat the cause of autoimmune diseases inman should identify B cell depletion as an attractivetherapy. The biological reagent (e.g. Rituximab), bind-ing to the B cell-specific molecule CD20, already existed

and was tried and tested in the treatment of non-Hodgkins lymphomas [1]. The results of B cell depletionin treating a number of diseases have been more thanpromising [2–4] and so far the predicted drawbackshave not materialised. The most obvious potential sideeffect is that the patient becomes immuno-compromisedand, therefore, susceptible to infection. The audit ofB cell-depleted patients does not indicate any increasedrate of infection, however, it is early days and much ofthe data derive from lymphoma patients. Still, it may bethat the observed maintenance of circulating antibodiesspecific for previous infections or vaccinations providessufficient protection [5]. However, if we are to depleteB cells from people over long periods, we should beaware of the many non-antibody related functions ofB cells and the potential ensuing effects if the B cellcompartment is ablated. In this short review, we willdemonstrate that B cell function in vivo is much morecomplex and diverse than simply making antibodies.B cells present antigen to T cells and then viamechanisms that involve both co-stimulation andcytokine production, they influence Tcell differentiationand then, finally regulate the T cell response.

Correspondence: Dr. David Gray, Institute of Immunology &Infection Research, University of Edinburgh, Ashworth Labs,King's Buildings, West Mains Road, Edinburgh, EH9 3JT, UKFax: +44-131-650-7322e-mail: [email protected]

Received 6/8/07Revised 10/9/07

Accepted 16/10/07

[DOI 10.1002/eji.200737728]

Key words:Antigen presenting

cells � B lymphocytes� Cytokines � Innateimmunity � Toll-like

receptors

Abbreviations: CIA: collagen-induced arthritis � PRR: patternrecognition receptors

David Gray et al. Eur. J. Immunol. 2007. 37: 3304–33103304

f 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu

B cell activation

As part of the adaptive immune system B cells carrysomatically re-arranged receptors (BCR) that they use torecognise, bind and internalise specific antigen. In mostB cells this means that they have a single specificity forantigen and can respond only to that antigen byinitiating a signal transduced into the cell via BCR-associated molecules such as CD79a and b. However,B cells can also be activated by a range of stimuli,independently of the BCR. For mouse B cells the classicmitogenic stimulus is lipopolysaccharide (LPS) [6], thatwe now know activates cells via a complex binding toLPS-binding protein (LBP), CD14 and Toll-like receptor(TLR) 4 [7]. Thus, LPS activation is a paradigm for thenon-antigen-specific activation of B cells via innatereceptors. Recently, it has become clear that B cellsexpress most TLR and can respond to a variety of TLRligands [8, 9], such as TLR2, TLR3, TLR5, TLR7 andTLR9. Their response to these stimuli can be toproliferate, to differentiate into antibody secreting cells,to become more efficient antigen-presenting cells(APC), or to secrete cytokines. Clearly, the responsesof B cells to antigens in their environment are not solelymediated through the BCR. Crucially, B cells, as with allother APC, can respond to broad classes of antigen(pathogen) via innate, pattern recognition receptors(PRR) and as a result influence immune activation in thevicinity. This means that the response of the one of themajor lymphocyte populations in secondary lymphoidtissues (up to 50% of cells) to pathogens expressingcombinations of PRR ligands is initially driven, not byAg-specific stimuli, but rather by the activation of PRR.

TLR activation of B cells and antibodysecretion

The idea, mentioned above, that B cells when activatedvia TLR differentiate to become antibody-producingplasma cells (T-independent responses) is not acontroversial one. However, in the last year or two,studies have been published, indicating that T-depen-dent antibody responses also require TLR activation ofB cells [10, 11]. The prevailing view prior to this hadbeen that antigen-specific signals, through the BCR, inconjunction with help from T cells (CD40 ligand +cytokines) were sufficient for B cells to make antibodiesto T-dependent antigens. The fact that T-dependentantibody responses are impaired in mice deficient inMyD88 (a TLR signalling adaptor protein) was thoughtto be due to a failure of Tcell priming in association withdendritic cells (DC). Now, Pasare and Medzhitov [10]have suggested that MyD88-signalling is required also inB cells. This conclusion has not been met with universal

approval. Nemazee and colleagues [12] have producedequally puzzling data to indicate that T-dependentantibody responses proceed quite normally in MyD88/TRIF double knockout mice that cannot transduce anyTLR signal. They propose that PRR stimuli other thanTLR are at work. The truth may lie somewhere inbetween, with particular subclasses of antibody beingmore or less dependent on TLR signals to B cells. Forinstance, several papers show that switching to theIgG2a isotype (IgG2c in C57BL/6mice) is determined byand may require TLR9 signalling [13–15]. Our own dataon this from chimeras in which the B cell compartment isMyD88-deficient, also show that the IgG2a response to avariety of antigens is severely impaired and interestinglyso is the IgM response (TB and DG, unpublished data),while all other IgG subclass responses are normal. TLR-mediated IL-6 production may be a significant driver ofthe IgM response [16].

TLR have been proposed to sustain long-lived serumantibody responses by stimulating (intermittently)differentiation of memory B cells into the long-livedbone marrow plasma cell pool [17]. Again, this iscontroversial as it circumvents the need for Tcell help forantibody secretion, with the attendant check onproduction of autoantibodies by somatically mutated,self-reactive memory cells. An alternative explanationmay be provided by the observation of D�rner,Radbruch and colleagues [18, 19] that the antigen-nonspecific plasma cells seen on boosting are the resultof mobilization of plasma cells from the bone marrowand not the bystander activation of memory cells. Theabsolute need for T cell help in the initiation ofautoantibody production has also been called intoquestion by Marshak-Rothstein [20] and Shlomchik[21] who have shown that co-ligation of BCR and TLR byautoantigen (e.g. DNA or RNA containing complexes)can cause autoantibody to be made, which in turnenhances delivery of Ab-autoAg complexes to TLR-containing processing compartment in plasmacytoid DC[22]. This will initiate autoreactive T cell activation andso amplify the autoantibody response. Interestingly, thedevelopment of autoimmunity (lupus), including auto-antibodies in BAFF-transgenic mice proceeds in theabsence of any T cells [23].

B cells as APC in vivo

The dogma thatmost B cells possess just a single antigen-specificity has led to the notion that B cells are onlyeffective APC for the antigen to which their BCR binds.This is largely true in vitro when B cells are given aprotein antigen for which they have no BCR specificity;they present it very poorly, especially in comparison toDC [24]. On the other hand they are just as efficient as

Eur. J. Immunol. 2007. 37: 3304–3310 Highlights 3305


DCwhen their BCR recognises the antigen [24]. This hasled to the perception that B cells do not contribute asAPC in primary responses, as there are too few antigen-specific B cells available. The role of B cells in primingTcells has long been controversial with data from B cell-deficient mice both for [25–27] and against [28, 29].Recently, data have appeared suggesting that B cells maycontribute surprisingly early. First, bone marrowchimeric mice, in which the B cell compartment lacksMHC class II, exhibit an impairment of T cell activationthat can be seen at very early time points (day 3)following immunization [30]. Secondly, in studies usingan mAb to detect specific peptide-MHC class II complexon the surface of APC, the appearance of presumablyimmunogenic material on B cells is within hours [31] oreven minutes [32] after intradermal injection of theantigen. Pape et al. [32] go on to show that follicularB cells acquire soluble antigen diffusing from thesubcapsular sinus in lymph nodes draining sites ofimmunization, in a process that does not requireintermediary DC. This stimulates them to move to thefollicular-T zone border where cognate interaction withTcells occurs [32]. The groups of Batista [33] and Cyster[34] have since shown that particulate (bacterial)antigens [33] and immune complexes [34] are alsopicked up by B cells in the region of the subcapsularsinus. In the spleen, marginal zone B cells have longbeen implicated in this process [35–37]; there are B cellsin lymph nodes that resemblemarginal zone B cells [38].It may also be significant that marginal zone B cells aredemonstrably the most efficient B cell APC [39]. None ofthis usurps the role of DC in initial priming of T cells;naive B cells are still generally thought of as tolerogenicin their interaction with naive T cells [40, 41]. However,it does suggest that very soon after infection/immuniza-tion (within hours, not days), B cells are activelycontributing to the antigen-presenting/T cell program-ming activity.

How can this be if frequencies of antigen-specificB cells are so low? Several possibilities spring to mind.(i) Antigen-specific or cross-reactive B cells exist athigher frequencies thanwe currently appreciate. (ii) Thelymphoid organs (especially the lymph nodes) aredesigned to allow the antigen-specific cellular interac-tions at very low frequency for the production ofantibody responses (proposed by Jenkins and colleagues[32]). (iii) B cells can take up and present antigen viareceptors other than the BCR. Thus, antigens that carryPRR (e.g. TLR) may be more effectively taken up byB cells. Antigen-nonspecific B cells have been shown, invivo, to acquire soluble protein, process and present it[42]. Furthermore, TLR ligands on the same particle andin the same endocytic compartment of APC enableefficient presentation to and activation of CD4 T cells[43]. This evidence does not address whether this is

related to enhanced Ag uptake, however, TLR11 and/orassociated molecules do seem to be involved in theuptake of the Toxoplasma gondii antigen, profilin [44].Interestingly, the recent demonstration of antigencapture by B cells in the subcapsule of lymph nodesand subsequent transport to the follicle is an antigen-nonspecific process, requiring the B cells to expresscomplement receptor 2 (CR2); however, there is noindication that the antigen is taken up, processed andpresented to T cells [34]. The basis in physiologicalreality of these possibilities needs much more investiga-tion. We have not considered here B cell presentation inthe establishment and perpetuation of autoimmunedisease; unfortunately it is beyond the scope of this briefreview; see the reviews [5, 45] for a proper treatment ofthe topic.

B cell cytokines and T cell programming

B cells, like other APC, have a programming function inT cell differentiation and this is mediated by thesecretion of cytokines. B cells are known to make awide range of cytokines [46, 47]. Lund and colleagues[46] have characterised cytokine-secreting B cells intosubsets similar to Th1 and Th2, so-called Be1 (makingIFN-c and IL-12) and Be2 (making IL-4) (Be = Beffector); both subsets make IL-2, IL-6 and IL-10 [46].The cytokine production by B cells, however, needs to bedistinguished as either “primary” or “secondary”.Primary production is elicited by primary stimuli, suchas TLR, while secondary production requires theinteraction of activated B cells with activated helperT cells. For instance, we can find no primary stimuli thatelicit IL-4 production by B cells; however, if they areallowed to interact with IL-4-secreting, activated Th2cells, they too will begin to make IL-4 [48]. In vivo thismay be important for the establishment of Th2immunity during infection [49]. We have found thatTLR ligands are themost potent stimuli for production ofcytokine by B cells and that this can be augmented byT cell-derived costimuli such as CD40L [8]. AlthoughB cells do make cytokines when both BCR and CD40 arestimulated, we find that the cross-linking of BCR onTLR-activated B cells is often an inhibitor of cytokineproduction [8].

Several models have provided evidence for theprogramming role of B cells in the development ofTh2 responses [50, 51]. The basis of this might be relatedto IL-4 production [48], to delivery of co-stimuli such asOX40L [26, 52] or ICOSL [53, 54] or their production ofIL-10 (down-regulating Th1 responses) [47]. The role ofB cells in the induction of other types of response hasreceived less attention. In relation toTh1 differentiation,B cells make very little IL-12; on a per cell basis, they



make 1000-fold less than DC [8], although one couldargue that this might be important if large numbers ofB cells are making it after polyclonal activation. B cellsalso make IFN-c in response to combinations of TLRligands (e.g. TLR2, 4 and 9), but not to single stimuli [8].It has been noted by Mastroeni and colleagues [55] thatB cell-deficient mice do not mount protective Th1responses to Salmonella typhimurium. Th1 developmentis also impaired in chimeras in which B cells do notexpress MyD88 and so is related to the TLR-mediatedactivation of B cells; however, it does not require them tomake IFN-c (TB and DG, unpublished observations).B cells make significant amounts of IL-6 in response to avariety of stimuli and exhibit TGFb message, althoughthe stimuli required for secretion of active TGFb have notbeen defined. Any role for B cells delivering these twocytokines in Th17 generation [56] remains to beinvestigated.

B cells are not homogenous and there are differencesin the propensity of different subsets to make cytokines.In relation to subsets, IL-10 has been most intensivelystudied. B1 B cells were the first to be recognised as IL-10producers [57] and this is reflected in the role ofneonatal CD5+ B cells in dampening acute inflammationin new born mice, by producing IL-10 [58, 59]. In adultmice, we find that marginal zone (MZ) B cells and B1cells produce most IL-10 in response to TLR ligands(TLR2, 4 and 9), while, in comparison, follicular cellsmake very little [8], an observation supported by otherlabs [60]. Other workers have suggested that transi-tional T2 B cells are the main IL-10 producers [61],although how this fits with their transient, differentiat-ing nature is unclear. Interestingly, in our hands, adichotomy in cytokine production exists as MZ B cellsmake IL-10 and no IFN-c, while follicular B cells makeIFN-c but no IL-10 [8].

B cells and regulation

B cells make both IL-10 and TGFb and thus couldconceivably be involved in the development of one of theregulatory T cell subsets. Dealing first with CD25+

FoxP3+ Tregs: the data in this area are limited,fragmentary and often contradictory; for instance inB cell–deficient mice there is no alteration in thenumbers or function of CD25+ FoxP3+ Treg [62], whilein Rituximab/B cell-depleted patients the numbers ofthese cells rise [63]. In some disease models evidencepoints to a positive role for B cells in the Treg control ofcolitis [64] and of EAE [65], in anterior chamber (of theeye) immune deviation (ACAID) [66] and in transplanttolerance [67]. In this last example, the authors raise thepossibility that B cells render Tcells (potential effectors)unresponsive and so, receptive to suppression by donor-

specific Tregs. Thus, the involvement of B cells in Tregfunction is not necessarily an inductive one, but mightinvolve a collaboration bringing about regulation or,recruitment of Treg to sites of inflammation, e.g. CNS[65]. It should be remembered that each model has itsown idiosyncrasies; for instance, in the NOD thyroiditismodel, B cell-deficient mice are resistant to diseaseinduction and the role of B cells in Treg function seemsto be negative. It is proposed that B cells sustain apersistent presentation of autoantigen (in B cell-suffi-cient NOD mice) that renders effector T cells resistant tosuppression by Tregs [62].

As discussed above the presentation of antigen bynaive/resting B cells is thought to render naive T cellstolerant [40, 41]. Recent data suggest that this tolerancemay result from the generation of Tregs [68, 69] with anunusual phenotype, (CD25+, CD62L+ and FoxP3–) [69].During the in vitro culture with naive T cells, the B cellsmake IL-10 although this is not required for thedevelopment of this Treg population [69]. It will beinteresting to know if TGFb is involved as small restingB cells express this cytokine [47]. In contrast, severalslightly older studies, showed that B cell-derived IL-10was crucial for the resolution of EAE [70], the delayedprogression of inflammatory bowel disease [71], andthe prevention of induction of collagen-induced arthritis(CIA) [72]. In all these cases the B cells involved wereactivated and consequently produced IL-10. How thisB cell-derived IL-10 production mediates these effectshas not been determined but the induction of a Tregpopulation seems most likely.

In relation to this, Gray et al. [73] have recentlylinked the immune suppressive activity of apoptotic cellson the development of CIA, with IL-10 production byB cells. The injection of apoptotic cells preventeddevelopment of CIA, a protection that was dependenton both B cells and on IL-10 [73]. A dissection of the cellinteractions indicated that apoptotic cells had a directeffect on B cells, which augmented their IL-10 produc-tion, which in turn caused the differentiation of apopulation of IL-10-producing T cells. B cells it seemsinduce Tr1 cells. It is worth noting that in theseexperiments the amount of IL-10 made by B cells(stimulated via TLR + apoptotic cells) is of a similarmagnitude to that made by the effector T cells and thusthe B cell-derived IL-10 is also likely to have effectsindependent of Tr1 cells. The unexpected link betweenB cell regulation and apoptotic cells raises the questionof whether the recognition of apoptosis during inflam-mation is a common feature in triggering a resolvingB cell cytokine response.



Concluding remarks

We are only beginning to understand the mechanisms bywhich B cells modulate T cell responses. At one extremewe may come to accept that innate (TLR?), non-BCR-mediated activation of B cells gives them the potential tobe a dominant APC population following infection withorganisms that carry TLR ligands. At the very least wecan be certain that TLR-mediated cytokine productionby B cells both drives T cell differentiation and regulatesits excesses (inflammation). We have highlighted herethe many non-antibody-mediated functions of B cellsand have focused mainly on their positive roles (seesummary in Fig. 1). In the light of these lessons, onemight be reluctant to ablate B cells from patients, but inautoimmune disease the balance is dramatically tippedtowards the very deleterious effects of B cell autoanti-body production and/or autoantigen presentation and,therefore, such drastic action is certainly warranted.However, these patients need to be followed carefully asthey may well tell us a more complete story of the waythat B cells contribute in the round to immune responsesand their modulation.

Conflict of interest: The authors declare no financial orcommercial conflicts of interest.

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