regulation of immunological memory

Regulation of immunological memory

David Gray

Hammersmith Hospital, London, UK

immunological memory can be regulated during either its development or its maintenance phases. Controversy and confusion surround both methods of regulation, especially in the field of T-cell memory. Recent work has helped in improving our definition of ‘a memory cell’, but this has been complicated by another major point of contention: whether memory cells are maintained by antigens or other stimuli. Unequivocal advances have recently been made concerning the molecular events involved in memory B cell generation in

germinal centers.

Current Opinion in Immunology 1994, 6:425-430

Introduction

Immunological memory is regulated at two levels: during its development or during its maintenance. An- swers to fundamental questions in these areas stil1 elude US and preclude a fuller understanding. We have a reasonably good idea how memory B cells develop but the differentiation pathways of memory T cells remain obscure. Do memory T cells develop via a separate pathway from effector T cells (as happens for B cells)? Are effector T cells end cells, or do they revert to memory cells? Immunological memory can last for a very long time, so it would be interesting to discover how long the actual memory cells live. At the moment there is controversy about the extent to which external factors influence lifespan of memory cells, and fmding a solution to this mystery is crucial. Despite evidente that memory cells can exhibit higher affinity receptors and have lower activation thresholds than naive cells, the overriding reason for augmented and accelerated memory responses is that the antigen-speciiìc precursor pool is vastly expanded in comparison with that available in the primary response. A further feature to be taken into account is the way in which the infecting organism interacts with its host. Whether an organism is cleared by the immune response or whether it can persist in the body, has profound consequences for the development and maintenance of memory. In addition, the immune system has its blind spots; memory is not generated if an organism ‘presents’ only carbohydrate moieties and memory can be evaded if the organism can mutate epitopes that form a dominant part of the response. This review considers some of the recent data relating to these questions and attempts to clar- ify the coniùsion that has developed on certain points.

Differentiation to memory B cells

The development of memory B cells is a T-cell dependent process; antigens that stimulate B cells in a T-independent marmer do not induce memory. Inter- estingly, although T cells can influence T-independent responses (e.g. by inducing isotype switching), they have no effect on the generation of memory to these antigens, suggesting that signals delivered during the cognate ET interaction are required for memory cel1 differentiation. As we shall see later, one of the crucial events for memory B cel1 development is the ligation of CD40 on the B-cel1 surface.

Memory B cells develop in germinal centers (GCS). These are foei of intense, antigen-driven proliferation that appear towards the end of the first week of the immune response. GCS are initiated by a smal1 number of precursor cells 111 that have almost certainly been activated previously in the T zones of secondaty lymphoid tissues 12,31. The T-zone proliferation is primarily involved in generating the primary antibody response, but a few of the cells activated there migrate to follicles and start to proliferate. The signals that initiate this process are not known; they might be delivered by specialized helper T-cel1 subsets 14.1 that colonize the area at the same time, or by follicular dendritic cells (FDCs) that form a structural network within the follicle. The T cells have a ThL-like phenotype, in that they produce interleukin (IL)-4 i4.1, and seem to be largely specihc for the immunizing antigen 15*,61. FDCs can prime B cells for a productive encounter with a T-helper cel1 (induction of B7 and increase in MHC class 11 expression) by delivering signals that include crosslinking

Abbreviations FDC-foliicular dendritic cells; GC-germinal center; HEV-high endothelial venules;

Il-interleukin; KLH-keyhole limpet hemocyanin; slg-surface immunoglobulin.

0 Current Biology Ltd ISSN 0952-7915 425

426 Lvmrhcvte activation and effector functions

of surface Ig (SI& by antigen on its surface and as yet UnidentiIìed antigen non-speciiìc signals 171.

The rapidly dividing GC B cells undergo somatic hyper- mutation of their V region genes 18-101. The elegant studies of Kelsoe and colleagues 111”l suggest that GCS are a unique and specialized site for somatic hypermu- tation; sequences obtained from T-zone foei are exclu- sively germline, while clonally related sequences derived from adjacent GCS are often mutated. The kinet- ics of mutation als0 support this conclusion; mutations appear first in sorted GC populations (E Källberg, D Gray, T Leanderson, unpublished data; 19,121). Within days of the start of GC proliferation some cells exit cel1 cycle and the GC becomes polarized to give a basal zone (dark zone’> of proliferating cells (centroblasts) and an apical zone (‘light zone’) of non-cycling cells (centrocytes). The centrocytes are susceptible to selection and in the absente of rescue signals rapidly die by apoptosis. The first step in the rescue of cells that stil1 have the capacity to bind antigen, is crosslinking of sIg by the antigen bound in immune complexes on the surface of FDCs 1131. This signal does not seem to be enough to confer long-term survival 114.1. Instead, further ‘secondary’ signals are required, and these probably also deliver programming instructions to the B cell, by inducing differentiation to plasma cells (CD23+IL-1, IL-2) or to memory cells (CD40-ligand) (reviewed in [14’,151).

The conclusion that CD40 signals are necessary for the development of memory B cells is now supported by direct, although unpublished, experimental data from two laboratories using similar approaches. In- jecting mice with either a soluble, chimaeric form of mouse CD40 U61 or hamster antibody to CD40 ligand (R Noelle, personal communication) has resulted in a considerable impairment of the development of memory B cells. The data from my laboratory indicate that the B cells are blocked at the earliest stages of their activation, and not later in the GC. Interestlngly, the only convincing studies of the histological localization of CD40 ligand expressing T cells places them in extra- follicular sites and not in germinal centers 1171.

Is there a separate lineage of memory B cells?

As we have already discussed, memory B cells proceed along a quite different pathway of differentiation from the cells that generate the primary antibody response. It is probably fair to say that most immunologists as- sume that these two sets of cells have common precursors which are pushed down one course or the other depending on the microenvironment in which they find themselves (i.e. the type of T cel1 or ‘accessory cell’ with which they interact). This view has been challenged by the studies coming out of the Klin- man laboratory over the past few years. These have distinguished a subset of B cells in mice before antigen exposure that participate in secondary antibody responses but not in primary responses 1181. These so-

called memory precursors give rise to germinal centers 1191 and accumulate somatic mutations 1181. However, the analysis of V gene sequences obtained from cells scraped from tissue sections [ll**l shows quite clearly that the cells proliferating in the primary T-zone foei are clonally related to those in GC. The lineage controversy awaits a satisfactory conclusion.

Towards a definition of memory T cells

A problem of interpretation has dogged most investi- gations of T-cel1 memory. How can memory T cells be distinguished from recently activated T cells and effector T cells? A plethora of surface molecules has been proposed as markers for memory T cells over recent years (reviewed in 115,2Pl). Most appear soon after activation and even the best of them (CD45RO) may not be stably expressed over long periods of time 121,22**1. Swain and colleagues 123’1, who are striv- ing to differentiate between naive, recently activated, memory and effector cells, make the very pertinent point that the definition can only lx made by con- sidering phenotype, activation state and analysis of function (including cytokine production and helper activity) 123’1. Analysis of the cytokines produced i?t vitro following in vivo priming or boosting reveals that resting memory cells look very much like naive T cells (they produce mainly IL-2 and IL-31, and that primary effector cells and memory effector cells produce a similar range of cytokines (in particular they make IL-4) and provide efficient help for IgG antibody responses 124’1. The fact that resting memory cells or memory effectors make five times more of their respective cytokines than do primary effectors is most probably due to the increased frequency of antigen-speciiìc cells in populations from primed mice. It is interesting that the switch to IL-4 production takes 3-4 days for both the naive cells and the resting memory cells, indicating there may be little differente in the activation threshold for memory cells. The published data from Swain’s laboratory 123’,24’1 concern the response to keyhole limpet hemocyanin (KLH) in normal mice: this sort of analysis is complex; interpretation of the data will be simpliiìed when known numbers of antigen-specific, T-cel1 receptor transgenic T cells can be sorted for in vitro analysis, following adoptive transfer and priming and/or boosting.

Migration of memory T cells

Many of the molecules for which naive/memory dis- criminatory claims have been advanced are involved in adhesion of T cells to other lymphocytes, accessory cells or endothelium 115,2@,251. One such molecule is L-selectin (MEL-14), which mediates binding of lymphocytes to high endothelial venules (HEV) in periph- era1 lymph nodes. L-selectin is lost during activation,

Regulation of immunological memory Gray 427

and memory cells are frequently said to be L-selectin negative 1230,251. This belief, in combination with the assettion that the only T cells entering lymph nodes by efferent lymph are memory phenotype 1261, has led to the notion that memory T cells do not enter lymph nodes across the HEV. This is an over-simplilìcation of the in vim situation that is elegantly revealed in the painstaking studies of Picker ef al. 127’1. The results show that the down-regulation of L-selectin following activation (measured by movement of the cel1 into the CD45RO population) varies according to the site from which those cells were originally derived. For instance, T cells from a peripheral lymph node show little over- all down-regulation of L-selectin, while those from the appendix do. This tissue-specific differential regulation is also demonstrated for cutaneous lymphocyte-associated antigen involved in the homing of T cells to the skin 1281. Clearly, memory T cells, in contrast to naive cells, are able to extravasate into the skin or the gut (reviewed in 120*,251). The tissue specificity arises out of the expression of particular adhesion molecules: skin- homing T cells expressing cutaneous lymphocyte-associated antigen (the receptor for E-selectin found on inflamed skin) 1291 and high levels of a4@ integrins (receptor unknown) 1301; and gut-homing T cells expressing high levels of a4B7 1311 (the receptor for MadCAM-1 found on mucosal endothelium) 1321. Al1 the discussion of adhesion molecules on memory T cells in the studies quoted here has to be tempered by the fact that the definition of memory is, in most cases, only phenotypic (see previous section).

long-term maintenance of memory

It has long been assumed that memory is sustained by long-lived lymphocytes. Evidente is now accumulat- ing, however, to suggest that T cells with a memory phenotype have a more rapid tumover than naive T cells 122”,26l. The most striking demonstration of this came from Michie et al. 122**1 when they repeated, with the benefit of the CD45RO antibody, a classic study 1331 that was in the past quoted as evidente for long-lived memory T cells. Chromosomal lesions that preclude cel1 division were followed with time after irradiation in CD45RA (naive phenotype) and CD45RO (memory phenotype) T cells. CD45RO cells with dicentric chro- mosomes disappeared from circulation within 1 year, indicating a relatively short interphase, while CD45RA cells survived without division for several years. There is also evidente from adoptive transfer experiments that naive T cells 1341 and B cells 1351 in mice have long lifespans.

On the face of it, the fact that memory cells tumover relatively quickly would appear to support the notion that the long-term maintenance of memory re- quires continued stimulation of one sort or another. We will discuss this in detail below, but we must first con- sider the proposal that memory cells revert to a resting state, in which they may not differ phenotypically from

naive cells. Certainly in rats 1211, probably in mice 136’1 and possibly in humans 122*‘1 there is a reversion from the memory phenotype to the naive CD45R isoform expression. Given the data on longevity of ‘naive’ cells, if memory cells do re-enter this population we have to conclude that they become long-lived. The problem with this scenario is that published experiments fail to demonstrate an enhanced, memory-type response from cells with a naive phenotype 1371. There are three possible explanations for this discrepancy. First, it can be argued that the in vitro assays do not fulfil the activation requirements of this ‘naive memory’ population. A second explanation might be that while stimuli are present within the body (antigen being the major one), memory T cells remain within the CD45RO population and are caused to cycle. As stimulation falls off, some or al1 of the cells enter the naive phenotype population and live a long life. This phase of the response has not been reached in most studies. By waiting long enough we might be able to detect memory within the CD45RA/RB population; however, we should keep in mind that the wait might be a long one, certainly longer than the life of a mouse. The reason for supposing this is that antigens on FDCs, that are available to stimulate B cells and CD4 T cells can be retained in complexes for more than a year 1371. Longitudinal studies of memory B cel1 turnover with time after immunization lend weight to this idea [39]. Finally, a third possibility is that the memory cells re-entering the naive-phenotype pool are smal1 in number; they do not provide an enhanced response but act to maintain a full repertoire of speci- ficities in the adult animal that may have minima1 input of new T cells from the thymus.

We have already touched on the role of antigen in maintaining memory populations over long periods of time. As Celada 1401 and Feldbush 1411 commented 20 years ago, antigen has a potentiating effect on memory, but is it an essential component in the survival of memory cells? The available evidente does not yield an unequivocal answer: the experiments in which memory B cells 1421 and T cells 1431 decay soon after adoptive transfer in the absente of antigen do not show be- yond al1 doubt that the rate of decay is more rapid than in the presence of antigen (although almost no decay was seen in the immunited animals). The lifespan of memory cells in the adoptive host, and almost certainly in u mnanipulated animals, is regulated by the expression of molecules, such as bc12, that influence the choice of the cel1 between life and death. For instance, when antigen-free transfers were performed with memory B cells from transgenic mice that over- express bc12, the memory response did not decay at all 1441. The factors that influence bc12 levels in memory cells are not known. Clinical experience shows that long-term memory is usually brought about by vita1 in- fections/vaccinations in which the virus or its genetic material may persist in the body; this is often accom- panied by the continued production of serum antibod- ies, an indicator that persistent stimulation is occurring. One of the predictions of the theory of antigen depen- dence on memory is that helper T cel1 memory would

428 Lymphocyte activation and effector functions

depend on a concommitant antibody response (to lo- calize antigen to FDC) and antigen-specific memory B cells (to recover antigen from FDC and present it). I’re- liminary experiments have shown that the rapid decay of antigen-specific T cells in severe, combined immun- odeficiency mice repopulated with T cells, in contrast to those repopulated with B and T cells, fùlfìls this pre- diction (Dullforce P, Matzinger l’, Gray D unpublished data).

It is not so easy to see a role for reservoirs of un- processed antigens in the maintenance of cytotoxic, CD8 memory. Several laboratories are now addressing this problem using virus infection models (influenza or LCMV which are quickly cleared and do not to persist in the host) or dendritic cells pulsed with major his- tocompatibility complex class 1 binding peptides. Only one study has been published so far [451; after adoptive transfer of T cells from influenza-primed mice, the cytotoxic memory response lasted undiminished for 25 weeks. The conclusion from this and other studies wil1 soon come to fruition: the survival of CD8 memory cells does not depend on antigen. This contradicts two earlier studies 143,461 and leaves many questions unan- swered, in particular concerning the influence of envi- ronmental stimulation (specifìc or cross-reactive) and of CD4 T cells in the persistente of CD8 memory.

Concluding remarks

The two major problems that hinder our progress to a more complete understanding of immunological memory are inextricably intertwined. To elucidate the pathway(s> of differentiation that give rise to memory T cells we have to distinguish them from recently activated cells and effector cells, preferably using multiple parameters. However, if antigenic stimulation carries on for a prolonged period of time, then the defmition of a discrete memory population wil1 be difficult; cells that transfer memory wil1 be phenotypically or func- tionally heterogenous during this period. We might have some chance of identifying true memory cells if we wait until this phase of the response is over; it can be accelerated using adoptive transfer techniques and the read out may be more reliably quantified if cells from Ig or T-cel1 receptor transgenics are used. These sorts of experiments, together with an increas- ing knowledge of the molecules involved in the regulation of cell death versus cel1 survival, should hasten advances in the field.

Note added in proof

The data referred to as R Noelle, personal communication, is now in press 1471.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as: . . .

1.

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4. .

of special interest of outstanding interest

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A comprehensive analysis by PCR of cytokine expression by CD57+ T cells found in humdn tonsillar GC. They prcxluce a lot of IL-4, but the other cytokines detected do not fit easily into a Th1 or Th2 phenotype.

5. Fuller KA, Kanagawa 0, Ndhm MH: T Cells Within Terminal . Centers are Specific for the Immunizing Antigen. J Immrrnoi

1993, 151:4505_1512. This experiment u.ses the fact that H-2h mice immunized with pi- geon cytochrome c prefentidlly use a VallNw combition of TcR V genes. The T-cell population of GC in cytochrome immune mice is enrlched for VallNBt)txpressing cells. The lmplication ls that cognate B-T intemction takes place here.

6.

7.

8.

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10.

ll. . .

Michie SA, Roux RV: Study of IMurine T Cell Migration Using the Thy-1 Allotype Marker. Transp~ntatfon 1988, 46:98-X%.

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Jacob J, Kelsoe G, Rajewsky K, Weiss U: lntraclonal Ge* eration of Antibody Mutants in Germinal Centers. Natwe 1991, 354389392.

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This painstaking study shows that B cells within the primary T zone foei of proliferation are not yet mutatlng but give rise to cells which migrate to GC and undergo mutation. The clonal relationships of cells withll the two sites are demonstrated.

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13. Liu Y-J, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan ICM: Mechanisms of Antigen-Drivcn Selection in Germinal Centers. Nutrtre 1989, 342:929931.

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The surface molecules that lymphocytes express following activation are influenced by the site in which they are activated. In this case, loss of L-selectin, thought to be a chamcteristic of memory cells, does not occur if the cells come from a peripheral lymph node. This is another considerdtion to take into account when phenotyping memory

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A comprehensive review of the field in geneml. See ah 1151.

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22. . .

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The data presented here have forced US to redefine trdditional ideas about the Ufespans of naive and memory cells. Cells with memoty phenotype are shown to turn over much more rdpidly than naive phenotype cells that live in interphase for years. 1 stress the word phenotype because of the possibility that memory cells reven, and resemble naive cells once more.

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k l24.1.

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This paper and l23.1 detail a set of complex experiments that go a long way in distiquishlng naive cells, memory cells and effector cells based on a variety of pammeters. Of particular interest is the analysis of cytokine production by these ‘subsets’.

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regulation of immunological memory

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