Review

Nature Clinical Practice Rheumatology (2008) 4, 43-49
doi:10.1038/ncprheum0671  
Received 13 August 2007 | Accepted 17 September 2007

Primer: making sense of T-cell memory

Peter CL Beverley  About the author

Correspondence The Edward Jenner Institute for Vaccine Research, Compton, Berkshire RG20 7NN, UK

Email peter.beverley@jenner.ac.uk

Summary

Protective memory is a key property of the immune system. Pathogen-associated molecular patterns of invading organisms deliver signals to pattern-recognition receptors that activate the innate immune system. Ligation of the T-cell receptor by peptides bound to MHC antigens and presented by dendritic cells, together with signals produced by the activated innate immune system, initiate T-cell responses. The nature of the T-cell response, consisting of phases of clonal expansion and contraction, and differentiation to effector and memory cells, however, is determined both by the properties of the antigen and the co-stimuli produced by the innate immune system. Short-lived effector and longer-lived memory T cells are generated during primary responses; after the death of most of the effectors, memory cells remain. Memory cells are heterogeneous in phenotype and function; subsets include the relatively quiescent central and more activated effector memory cells, as well as cells able to promote inflammation, help antibody production or regulate other immune responses. Understanding the properties of memory cells will help in the rational design of vaccines for 'difficult' organisms or cancer, as well as immunotherapies for autoimmune diseases.

Review criteria

This article is based only on work published in the English language. Information was drawn from the older literature on the basis of the author's experience in the field. PubMed searches used single or combinations of keywords including "antigen", "apoptosis", "contraction", "cytokines", "cytotoxic", "expansion", "helper", "memory", "T cell" and "turnover" were performed. Where possible examples are drawn from human studies rather than from studies using experimental animals.

Keywords:

cytokine, effector, lymphocyte, memory, protection

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Introduction

Memory and specificity are defining features of adaptive immunity. Immunological memory is the ability of an animal to make a second, more effective, immune response to an antigen that has been encountered previously. The discovery of cell-surface markers that distinguish cells that have previously encountered antigen from those that have not (naive cells), and the ability to detect antigen-specific cells after immunization, using MHC-peptide tetramers or multimers, made it possible to identify 'memory populations' or 'memory cells'. The latter can be defined as clones of lymphocytes that have expanded on contact with antigen and acquired new phenotypic characteristics (Table 1).

Table 1 Properties of naive, effector and memory T cells.a
Table 1 - Properties of naive, effector and memory T cells.a
Full tableFigures & Tables indexDownload PowerPoint slide (122K)

This definition sounds straightforward, but many questions surrounding the nature of memory T cells remain. First, the term 'memory' implies persistence in the absence of antigen, yet the highest frequencies of antigen-specific 'memory' cells are found in persistent virus infections, although as these cells are continuously exposed to antigen it is debatable whether they should be termed 'memory' cells. Second, many members of expanded populations (clones) are clearly short-lived effector cells,1 although the exact lineage relationship between these cells and longer-lived memory cells is itself a matter of debate.2 Finally, after clonal expansion, some T cells might revert to a state indistinguishable from naive cells, although whether significant numbers of such revertants exist remains to be proved.3 It is clear, however, that most protective (or pathogenic) T lymphocytes are members of expanded clones with distinct phenotypic and functional characteristics, so that the term 'memory' will be used to indicate these cells or populations, irrespective of whether antigen remains present.

This Review will focus on T cells with alphabeta T-cell receptors (TCRs), from which the essential CD4 and CD8 effector cells are derived; without the former cell type, normal antibody production is impossible. Furthermore, there is much interest in producing a new generation of vaccines aimed at inducing cellular (T cell) immunity to combat difficult diseases such as cancer, AIDS, malaria and tuberculosis. T cells expressing gammadelta TCRs will not be considered further, because they might be more closely allied to the innate than to the adaptive immune system, and it remains unclear whether they exhibit immunological memory.

Rearrangement of gammadelta and alphabeta TCR genes takes place in the thymus. Before T cells leave the thymus, selective events delete cells with receptors that have high affinity for self-peptides presented by MHC antigens, while cells with TCRs with moderate affinity are retained, allowing a response to take place when bound foreign peptides are presented to these cells. The specificity and affinity of T-cell memory populations are determined by the selection of TCRs from among this predetermined pool of naive TCRs.

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How is memory generated?

Initiation of immune responses

Antigen entering the body is carried in afferent lymph to draining lymph nodes or taken up by peripheral dendritic cells (DCs), which are stimulated to migrate to the lymph nodes. There antigen is processed to short peptides and presented by DCs on MHC class II and class I molecules to initiate the responses of naive CD4 and CD8 T cells.4 TCR signals alone, however, are tolerogenic, and effective immune responses are only initiated in the presence of co-stimuli delivered by surface molecules of DCs, such as CD40, CD80 and CD86, to their T-cell counter-receptors, CD154, CD28 and CD152. DCs and other cells of the innate immune system also produce stimulatory cytokines and chemokines. The spectrum of signals produced by innate immune cells is in turn determined by pathogen-associated molecular patterns, which stimulate these cells via conserved pattern-recognition receptors. These include Toll-like receptors, lectin-like receptors, nucleotide oligomerization domain-like receptors and retinoic acid inducible-like receptors.5, 6, 7, 8 Integration of these innate system-derived signals determines the fate of responding T cells; however, DCs are also heterogeneous in phenotype and function, providing a further level of regulation.9

T-cell clonal expansion

The magnitude of the initial T-cell response is an important determinant of the duration of memory10 and is partly determined by the number and affinity of naive antigen-specific precursors.11 Delivery of a TCR signal with appropriate co-stimuli leads to clonal expansion, but the effects on CD4 and CD8 T cells differ. CD8 T cells stimulated for 24 hours in vitro and transferred into antigen-free hosts undergo at least seven divisions and acquire effector and memory function—the 'autopilot' concept.12 Co-stimuli and cytokines, however, also influence CD8 proliferation and differentiation.13 By contrast, although a short pulse of antigen can initiate limited CD4 cell division, continuous antigen exposure is essential for proliferation and differentiation of these cells in vitro and in vivo.14 Even under these circumstances, responding CD4 T-cell frequencies are lower, and the size of individual CD4 clones smaller, than those of CD8 cells15, 16, 17 (Table 2; Figure 1). Underlining the importance of prolonged exposure, antigens that are resistant to lysosomal degradation potentiate proliferative responses of CD4 T cells,18 and during viral infections, in which antigens are presented for extended times, high numbers of CD8 T cells are generated.1, 19 Clone size is limited by cell death as well as by the extent of proliferation.20

Figure 1 Kinetics of T-cell responses.
Figure 1 : Kinetics of T-cell responses. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Clonal expansion is controlled by the dose and persistence of antigen, and by the amount and nature of innate immune system co-stimulatory signals generated by pathogen-associated molecular pattern stimulation. CD8 T-cell expansion and contraction is very rapid, so that memory is rapidly established. In contrast, CD4 T-cell memory is only fully established after a prolonged clonal contraction phase.

Full figure and legend (14K)Figures & Tables indexDownload PowerPoint slide (87K)

Table 2 Numbers of antigen-specific naive, effector and memory T cells.a
Table 2 - Numbers of antigen-specific naive, effector and memory T cells.a
Full tableFigures & Tables indexDownload PowerPoint slide (172K)

Clonal contraction and generation of memory

The peak of the proliferative response to antigen is reached within 1–2 weeks, and there follows a phase of contraction, in which most short-lived antigen-specific effector T cells die by apoptosis. After the loss of these short-lived effectors, a population of longer-lived memory cells remains1, 12, 21 (Figure 1). CD4 cells have slower kinetics and expand less than CD8 cells; CD4 cells show a biphasic pattern of contraction, whereas CD8 cells show massive and rapid expansion and collapse, followed by life-long preservation of a stable memory population, at least in relatively protected experimental animals.16, 22

How and at what stage of the T-cell response effector and memory fate are specified remains a matter of debate. It is possible that each cell is programmed by its initial contact with a DC (the 'one cell, one fate' theory). Alternatively, the progeny of a single cell might acquire distinct programs by two different means. Because there is polarization of the signaling and cytoskeletal molecules induced by contact between responding T cells and DCs, unequal cell division and partitioning of molecules might occur.23 Different programs might also be induced after one or more cell divisions because cell progeny enter different microenvironments (the 'one cell, multiple fates' theory).2 In either case, early in the encounter of T cells with antigen-presenting cells, under the influence of cytokines and chemokines, death receptors and proapoptotic proteins such as CD95 (FAS; also known as tumor necrosis factor receptor [TNFR] superfamily member 6) and BCL2-like protein 11 (BIM) are rapidly upregulated, leading to T-cell death. Survival of memory T cells requires expression of the antiapoptotic protein B cell leukemia/lymphoma 2 (BCL2).24, 25 As well as survival genes, upregulated expression of T-box transcription factor 21 (TBX21, also known as T-bet, or T-box expressed in T cells) and eomesodermin is responsible for the continued expression of CD122, the interleukin (IL)-15 receptor alpha chain, which has an important role in promoting memory CD8 differentiation and maintenance.26 Early expression of the IL-7 receptor alpha chain (CD127), which was originally thought to identify potential CD8 memory cells, is not essential.21 In CD4 T cells, human immunodeficiency virus type I enhancer binding protein 2 (HIVEP2, also known as Schnurri-2) is thought to be important for effector-to-memory transition.27

In addition to signals derived from the innate immune system, CD8 T cells require CD4 T cells. Although CD8 effectors can be produced in a primary response in the absence of CD4 T cells, memory CD8 cells generated in their absence make poor responses when re-stimulated and die by activation-induced cell death, mediated via the TNF-related apoptosis-inducing ligand (TRAIL, also known as tumor necrosis factor [TNF] ligand superfamily member 10). Exactly what CD4 cells provide for CD8 memory cells remains to be elucidated.28

Maintenance of T-cell memory

Memory in humans persists for decades29 but, paradoxically, the average lifespan (the time to death or the next cell division) of individual memory cells is shorter than that of naive cells.30 Although the duration of memory is determined by the survival of expanded clones, not individual cells, clonal exhaustion could limit the duration of memory because the proliferative capacity of somatic cells is finite and limited by telomere shortening at each cell division. This shortening might be expected to occur during clonal expansion as well as during division of memory cells; however, during immune responses, expression of telomerase is upregulated, and telomeres lengthen.31 This process has the important consequence that cells entering the memory pool do so with long telomeres and unimpaired proliferative capacity.

IL-7 and IL-15, whose receptors share a common gamma chain, have been shown to be important for memory cell survival using transgenic and knockout mice, and blocking antibodies. IL-15 is essential for memory CD8 T-cell survival, and although there is no absolute need for IL-7, it can compensate for the absence of IL-15.32 In mouse experiments, the number of CD8 memory cells, when transferred to hosts that are antigen free or lacking MHC class I molecules, declines only very slowly over time, showing that antigen is not required for maintenance of CD8 memory.33 By contrast, evidence suggests that both TCR signals and IL-7 are required for CD4 memory cell survival.34 In addition, tissue signals, such as those delivered by TNFR family molecules, contribute to survival of memory cells in 'memory' niches.35

Animals and humans are continually exposed to new antigenic challenges, and new memory populations are produced (Table 2). As immunological space is finite, there must be competition for survival within the memory pool. Antigen or cross-reacting antigen36 can provide an advantage in this competition, and it is notable that the highest frequencies of 'memory' cells are those found in chronic systemic viral infections, such as those caused by lymphocytic choriomeningitis virus, Epstein–Barr virus, cytomegalovirus and HIV.1, 19, 37 'Memory' cells in these chronic infections have differing phenotypes, which reflect altered and sometimes compromised function:19, 37 CD8+CD45RA+CD27- effector memory cells, which are increased in cytomegalovirus infection, have unusual kinetics and poor effector function, and HIV memory cells express the programmed cell death late activation antigen PD-1 and are 'exhausted'.38, 39 Whether in long-lived species, such as humans, useful memory clones can persist for life in the absence of continuing antigen exposure, or alternatively, memory is dependent on continual recruitment of new clones from the naive pool, remains to be resolved; however, in contrast to what is observed in mice, in humans both CD4 and CD8 memory responses to vaccinia virus decline slowly over time, with a half life of 8–15 years.29

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Heterogeneity of memory T cells

Central and effector memory

Expression of the molecules CD27, CD62L and CCR7 distinguishes central memory cells (TCM) from effector memory cells (TEM). TCM readily enter lymphoid tissues, proliferate vigorously on re-encountering antigen and generally produce cytokines or develop cytolytic functions slowly. These properties, together with the long telomeres and relatively slow turnover of this subset, indicate that TCM provide a reserve of long surviving clones able to respond with vigorous secondary responses to a re-encounter with antigen. By contrast, TEM proliferate less well, have shorter telomeres, produce cytokines rapidly, and readily enter nonlymphoid tissues, providing immediate protection against re-infection (Table 1).40, 41 The lineage relationship of these subsets and whether conversion between them is freely possible have been much debated.21, 28 It has also been argued that only effector memory is evolutionarily relevant because only TEM can provide protection against re-infection, although this is not a widely accepted view.42

Although TCM predominantly re-circulate between blood and lymphoid organs, TEM leave the blood to enter nonlymphoid tissues and are found predominantly in nonlymphoid sites. More recently, it has been shown that CD8 TCM can also enter nonlymphoid tissues, and when they do so they convert to TEM,43 confirming other evidence that tissue microenvironments influence the phenotype of lymphocytes; for example, virus-specific gut intraepithelial lymphocytes resemble neither TCM nor TEM.44 In addition to the propensity to enter lymphoid or nonlymphoid tissues, T cells also exhibit a further degree of tissue specificity, so that T cells primed in mesenteric lymph nodes migrate better to the gut and those primed in peripheral nodes home better to peripheral tissues. These migratory patterns are imprinted on T cells by DCs from each type of lymph node and depend on upregulation of homing molecules.45

Patterns of cytokine production

CD4 T helper 1 (TH1) cells secreting interferon-gamma, TNF and IL-2, and T helper 2 (TH2) cells secreting IL-4, IL-5, IL-10 and IL-13, were the first helper subsets to be described, but subsequently T helper 17 (TH17) and regulatory T cells (TREGS) have been added to the list of major CD4 T-cell subsets. Although many TREGS differentiate in the thymus, others are highly differentiated members of antigen-specific CD4 T-cell clones.46 Furthermore, all four of the above mentioned T-cell subsets can be generated from mouse naive CD4 T cells by delivery of appropriate signals (Figure 2). TH1 cell differentiation depends on IL-12 and TH2 cell differentiation on IL-4, both produced by DCs. TH17 cell differentiation, which was thought to be dependent on IL-23 rather than IL-12, has now been shown to depend on transforming growth factor beta and IL-6, although in humans IL-1beta and IL-23 are also required.47, 48 Culture of naive T cells with transforming growth factor beta alone generates TREGS. The balance of these subsets is thus controlled by signals from DCs and other innate system cells, which induce the expression of signature lineage-determining transcription factors.49

Figure 2 Programming of mouse helper T-cell subsets.
Figure 2 : Programming of mouse helper T-cell subsets. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Differentiation of CD4 memory and effector T-cell subsets is controlled by cytokines produced by the innate immune system. These activate key transcription factors, which in turn program the ability to produce effector cytokines. Abbreviations: FOXP3, forkhead box P3; GATA3, GATA binding protein 3; IFN-gamma, interferon gamma; IL, interleukin; RORgammat, retinoic acid receptor-related orphan receptor gammat; TBX21, T-box transcription factor 21 (also known as T-bet, or T-box expressed in T cells; TH1, type 1 T helper cell; TH2, type 2 T helper cell; TH17, type 17 T helper cell; TGF-beta, transforming growth factor beta; TREG, regulatory T cell.

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TH1 and TH2 cytokines are broadly associated with cellular and humoral immunity, and TREGS have important immunomodulatory activity. TH17 cells were first identified because they potentiated pathology in autoimmune disease models but, along with granulocyte colony-stimulating factor, IL-17 stimulates the development of granulocytes, so TH17 cells are most probably important in bacterial infections.49, 50, 51 Although each subset of T cells is associated with a pattern of cytokine production, single cells show much more variability, and the number of cells producing distinct combinations of cytokines changes over time during an immune response.50 The importance of qualitative and quantitative differences in patterns of cytokine production by single cells, however, remains to be fully established.52, 53

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Conclusions

Much evidence suggests that the extent of clonal expansion and contraction, the generation of effectors and the phenotypic, functional and migratory properties of memory cells are imprinted early in the interaction of T cells with antigen-presenting DCs. Furthermore, the magnitude of the initial immune response has an important influence on the duration of memory.10 These observations suggest that targeting the early phase of the response by manipulating the duration of antigen exposure and the co-stimulatory signals delivered to pattern-recognition receptors might be the most effective means to optimize immunization. Since the contraction phase is equally important in determining the number of cells that enter the memory pool, preventing cell death is an alternative strategy.21, 54 On the other hand, it is also clear that local microenvironments can modulate the phenotype and function of mature memory T cells, indicating that immunotherapeutic interventions to modulate ongoing immune responses in autoimmune diseases or chronic infections should be possible.

Interesting results have recently been obtained by targeting PD-1 or its ligands, PDL-1 and PDL-2. PD-1 is inducibly expressed on T and B cells, natural killer cells and monocytes, while PDL-1 and PDL-2 can be expressed on DCs, macrophages and other tissues and cell types, and are also regulated by cytokines.55 The kinetic properties of memory cells offer further possibilities for intervention, as depletion of dividing T cells has been shown to be capable of ablating T cell memory while sparing naive T cells,56 and determination of the half-life of decline of CD4 T cell memory has established an important parameter for guiding vaccination schedules.29

Finally, although rational manipulation promises to allow the generation of ever stronger and longer-lived immune responses,57 it is important to caution that 'more is not necessarily better' and that the aim of vaccination is to generate protective immune responses, not just immune responses.42 The complexity of peripheral T cell subsets and their interactions suggests that in addition to understanding how to generate larger responses, understanding how to achieve the right balance of different T cells will be the key to producing successfully a new generation of prophylactic vaccines for 'difficult' pathogens or cancer, and for designing successful immunotherapy for chronic autoimmune or infectious diseases.

Key points

  • T-cell memory consists of expanded clones of cells that differ in phenotype from naive T cells and turn over more rapidly
  • Pathogens deliver signals to the innate immune system, which influence the nature of developing memory cells early in an immune response
  • The magnitude of a memory population is determined by the nature, dose and persistence of the antigen
  • Memory cells compete for survival, and antigen or cross-reacting antigen provides a survival advantage
  • Memory cells are heterogeneous in kinetics, homing and function; their function can be modulated by their microenvironment

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Acknowledgments

PCL Beverley is supported by a fellowship from the Jenner Foundation.

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Competing interests

The author declared no competing interests.

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Subject areas under which this article appears: Immunology