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Keywords:

  • Allografts;
  • alloimmunity;
  • T lymphocytes

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

The adaptive immune system is endowed with long-lived memory to recall previous antigen encounters and respond more effectively to them. Memory immune responses are mediated by antigen-specific memory T lymphocytes that exhibit enhanced function compared with naïve T cells that have never encountered antigen. While the generation of memory T cells specific for pathogens is beneficial in providing protective immunity, memory T cells specific for alloantigens can be deleterious to the recipient of a transplanted organ. In graft rejection, memory T cells mediate accelerated, ‘second-set’ rejection and their presence has been associated with increased propensity for early rejection. Recent findings have demonstrated that alloreactive memory T cells can be generated via exposure to alloantigens, as well as stimuli that are cross-reactive with alloantigens, and are therefore likely present in ‘naïve’ individuals. This review focuses on the characteristics of memory T cells which make them of special interest to the transplant community, including differential activation requirements, broad homing properties, and resistance to tolerance induction. The multiple ways in which memory T cells can contribute to early and late graft rejection are discussed, as well as potential targets for combating alloreactive memory to be considered in the future design of tolerance induction strategies.


Abbreviations:
TCR

T-cell receptor;

APC

antigen-presenting cell;

EBV

Epstein-Barr virus.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

An individual's history of antigen exposure is recorded within the long-lived antigen-specific memory T and B lymphocytes that comprise the memory immune response. When a previous antigen is encountered, memory T lymphocytes are rapidly mobilized to deliver a recall response that surpasses a primary response to new antigens in speed, magnitude and efficacy. This enhanced memory response is often beneficial, and can provide protective immunity against recurrent pathogens; however, in transplantations the presence of memory immune cells specific for alloantigens is potentially deleterious. Memory T cells are known to mediate the classic ‘second-set’ or accelerated rejection observed in primed recipients (1,2), and their presence in transplant recipients has more recently been linked to an increased propensity for early rejection episodes (3). Recent findings on memory T cells have revealed remarkable heterogeneity and diversity in function and migration that suggest a broad role for memory T cells in both early and late graft rejection. Here, we will review novel properties of memory T cells, their potential role in graft rejection, and will discuss how optimizing strategies for inducing transplantation tolerance should include the targeting of memory T cells.

Adaptive immune responses to environmental antigens, pathogens or alloantigens are triggered by the activation of naive T cells via contact of the T-cell receptor (TCR) with specific antigen/MHC molecules presented by an antigen-presenting cell (APC), together with a costimulatory signal also supplied by the APC. This two signal activation triggers the proliferation and subsequent differentiation of naïve T cells into effector T cells that secrete myriad cytokines to recruit and activate additional immune cells, such as B cells for antibody production, and macrophages for antigen clearance. Most of these activated/effector T cells die after a brief lifespan, although a small proportion of previously activated cells persist and develop into long-lived memory T cells, which mediate potent recall responses when reactivated by antigens. Memory T cells are heterogeneous and two memory subsets have been recently identified in humans and mice designated ‘central memory T cells’ that migrate primarily to lymphoid tissue, and ‘effector-memory T cells’ that migrate to both nonlymphoid and lymphoid tissue (4,5). It is not known whether memory T cells or subsets derive directly from differentiated effector T cells or from activated, pre-effector intermediates (6). The complement of long-lived T lymphocytes within an individual thus comprises both naive and memory T cells, with the proportion of memory T cells increasing with age, reflecting an accumulation of antigenic experiences. The additional heterogeneity of memory T cells in phenotype, function and homing capacity, adds to the complexity of the T lymphocyte compartment. In transplantation, where graft survival critically depends on suppressing T-cell-mediated immunity, it is important to consider the mosaic of activation histories and functional capacities of the memory T-cell pool in understanding the pathogenesis of graft rejection and in designing new and more effective immunosuppression strategies.

Generation of alloreactive memory cells

It is well known that all individuals possess a high precursor frequency of T cells that exhibit alloreactivity (7,8) and can potentially respond to an allogeneic transplant; however, considerably less is known regarding the frequency of alloreactive memory T cells among individual recipients. An individual who has received a prior allogeneic stimulus via a blood transfusion, previous transplant, or pregnancy would be expected to contain alloreactive memory T cells. In support of this idea, Lechler and colleagues demonstrated the presence of primed alloreactive T cells in all chronic renal failure patients studied that had received blood transfusions or prior transplants (9). However, individuals that lack prior alloantigen sensitization also contain alloreactive precursors within the memory T-cell population (10,11). Generation of allo-specific memory independent of direct alloantigen exposure likely arises via heterologous immunity, in which memory T cells generated following exposure to one antigen such as a pathogen, cross-react to and become activated by exposure to a second unrelated antigen, such as an alloantigen. In mice, it has been shown that a proportion of memory T cells generated as a result of infection with lymphocytic choriomenigitis virus (LCMV) or the Leishmania parasite also exhibit alloreactivity (12–14). Heterologous immunity also occurs in humans. In EBV infection, Burrows and colleagues have shown that the majority of HLA-B8+ EBV-seropositive individuals contain CD8 memory T cells specific for the alloantigen HLA-B*4402 (15), and that EBV-specific human CD8 T-cell clones exhibit alloreactivity (15,16). Conversely, alloantigen-specific human CD4 and CD8 T cells can exhibit reactivity to nonrelated proteins (17). Thus, it is likely that a majority of ‘naïve’ individuals that never encountered a prior allogeneic stimulus, contain circulating alloreactive memory T cells, and that the response to alloantigen involves the participation of naïve as well as memory T cells (11).

Distinguishing Features of Memory T Cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

Antigen-specific memory T cells mediate enhanced responses compared with naive T cells, owing to both quantitative and qualitative factors. Quantitatively, clonal populations of antigen-specific memory cells can exist for many years, far outnumbering the precursor frequencies of antigen-specific naive T cells (18,19). However, even when numbers of antigen-specific naive and memory T cells have been rigorously controlled for, memory cells have distinct advantages over naive cells in combating a recurrent antigenic encounter (see Table 1 and below), which may play important roles in initiating early and potent responses against an allograft.

Table 1.  Properties that distinguish naive and memory T cells
PropertyNaive T cellMemory T cell
Phenotype (73)CD45RBhi (mouse)/CD45RA (human)CD45RBlo (mouse)/CD45RO (human)
 CD44loCD44hi
 CD11aloCD11ahi
 CD62LhiCD62Llo/hi
 CCR7hi (human)CCR7lo/hi
Costimulation requirements (58)
(CD28/B7; CD40/CD154)MandatoryDispensable
Antigen-presenting cells (33,34)Professional (dendritic cells)Non-professional:
  e.g. resting B cells, endothelial cells
Response to low antigen dose (32)WeakStrong
Effector function (22)None (produce IL-2)Effector cytokines, cytolysis (CD8)
Kinetics (29,32)Slow (days)Rapid (hours)
Homing (5,74)Lymphoid tissueLymphoid and non-lymphoid tissue
Heterogeneity (4,23,25)Unknown, relatively homogenousMultiple subsets
Ability to tolerize (55)Amenable; e.g. costimulation blockadeDifficult

Cell surface phenotype and homing properties

Memory T cells exhibit surface phenotypic markers that distinguish them from naïve counterparts and also reflect their enhanced functional and migration properties. The enhanced expression of activation markers such as CD45RO, and adhesion molecules such as LFA-1 (CD11a) and CD44, on memory vs. naïve T cells (Table 1) are thought to promote efficient interactions with APC and extravasation into inflammatory sites (20–22). More recently, expression of the lymph node homing receptors CCR7 and CD62L have been found to vary among memory T cells (4,23). In general, expression of CCR7 and CD62L is high in naive cells, connoting their preferred trafficking to lymphoid tissue (24), whereas memory CD4 and CD8 T cells comprise heterogeneous populations of CCR7+/CD62Lhi and CCR7/CD62Llo subsets (Table 1) (4,23). These phenotypic distinctions have been shown to delineate functional subsets of memory T cells, designated central memory (CD62Lhi/CCR7+) and effector memory (CD62Llo/CCR7) (4). The CD62Lhi/CCR7+ memory CD4 T-cell subset from human peripheral blood was found to lack effector function and produce primarily IL-2 (4), although virus-specific human and mouse central memory CD4 and CD8 T cells were found to exhibit ample effector function (25,26). In vivo, central memory CD8 T cells yielded greater protective immunity to LCMV infection in mice compared with the effector-memory subset (25). Therefore, the effector capacity of memory subsets that differ in homing receptor expression may likely differ according to the antigenic system. It will be important in future studies to establish the respective roles of central and effector memory T cells in allograft rejection.

These variations in homing receptor expression on memory T cells reflect their broad tissue distribution in both lymphoid and nonlymphoid sites including lung, liver, kidney, intestine, and also the brain (5,27). It has been shown that memory CD8 T cells in peripheral tissues, unlike memory CD8 T cells in lymphoid tissues, can spontaneously lyse target cells upon antigen reencounter, without the need for clonal expansion and differentiation (5). Thus, memory T cells have an ‘anatomic advantage’ over naive cells in that they are poised to exhibit immediate function at the site of antigen reencounter, bypassing the need for antigen presentation in the local lymph node. In graft rejection, Lakkis and colleagues have directly demonstrated the relevance of this memory cell advantage by showing that allospecific memory T cells, but not naive T cells, can efficiently reject cardiac allografts in the absence of secondary lymphoid tissue (28). Thus, memory T cells may have the potential for mediating early rejection responses owing to their rapid trafficking.

Activation requirements and function

On per cell basis, antigen-specific memory T cells have less stringent activation requirements and exhibit enhanced activation compared with antigen-specific naive T cells. These properties have been demonstrated using T cells isolated from TCR-transgenic mice (TCR-tg) in which a majority of CD4 or CD8 T cells express a defined TCR specific for a given peptide antigen/MHC complex. Using TCR-tg systems, it was found that CD8 memory T cells specific for alloantigen exhibit rapid effector function, faster proliferation, increased responses to low antigen doses and direct cytolytic activity compared with allospecific naive CD8 T cells (29,30). Similar analyses have not been accomplished using alloantigen-specific TCR-transgenic CD4 T cells, although TCR-tg CD4 T cells specific for nominal antigenic peptides likewise exhibit immediate effector responses at low antigen doses (31,32). Memory T cells therefore have a kinetic and dose–response advantage over naive T cells.

Memory T cells also have less stringent activation requirements and are more permissive to activation by different APCs (Table 1), compared with naive counterparts. Naive T cells require CD28/B7-mediated costimulation (signal 2) provided by professional APCs such as dendritic cells; however, memory T cells can be fully activated in the absence of costimulation via the B7/CD28 or CD40/CD154 pathways, and by many nonprofessional APC types such as resting B cells and macrophages (Table 1) (33,34). Moreover, Pober and colleagues have shown that memory, but not naive, allogeneic CD8 T cells can become activated, expand, and differentiate into cytotoxic T cells by coculture with endothelial cells (34). When taken together, it is clear that memory T cells, owing to their unique trafficking patterns, reduced activation requirements, and instantaneous recall may not only be the vanguard of T cells to arrive in an allograft, but are also capable of rapidly initiating endothelialitis and vascular rejection.

Effect of Memory T Cells on Allograft Survival

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

The critical role of T cells in ‘second set’ rejection has been established by the demonstration that accelerated rejection of secondary allografts can occur in alloantigen-primed animal models in the complete absence of B cells and circulating antibody (1,35). In patients, the presence of alloreactive memory T cells has been more difficult to assess. Sensitized transplant recipients are typically identified based on the presence of circulating anti-HLA antibodies, and it is well known that highly sensitized individuals have increased rejection episodes and inferior graft survival compared with unsensitized recipients (36–38). Because T-cell activation is necessary to provide ‘help’ as a prerequisite for B-cell activation and subsequent antibody production, it is likely that these sensitized individuals possess allospecific memory T cells. Heeger and colleagues have directly demonstrated the presence of primed allospecific memory T cells in transplant recipients using a sensitive ELISPOT assay based on cellular quantitation of effector cytokine producers (39). Using this assay, they provide evidence, in a small cohort of patients, that the pretransplant frequency of primed, donor-reactive cells in recipients of living donor kidneys correlates with the post-transplant risk of developing acute rejection episodes (3). These studies suggest that the presence of alloreactive memory T cells may impact survival of an allograft.

A major question that emerges when considering memory T cells in the transplant recipient is whether memory T cells are equally susceptible to current immunosuppression regimens. While little is known concerning the effects of immunosuppression on immune memory, the distinct signaling, cytokine, and survival requirements of memory vs. naive T cells suggest that memory T cells and/or memory subsets may be differentially affected by specific immunosuppressants. For example, both mouse and human memory T cells exhibit distinct TCR-mediated signaling compared with naive T cells (40–43), potentially affecting their susceptibility to cyclosporine and tacrolimus, which both target the TCR-coupled signaling pathway leading to IL-2 gene transcription. In addition, priming for memory recall responses has been shown to occur in vitro in the presence of cyclosporine (44), raising the possibility that alloreactive memory T cells could be generated in immunosuppressed individuals.

Other immunosuppressants that target cytokine responses may also differentially affect naive vs. memory T cells. While IL-2 is involved in the clonal expansion of naive T cells, memory CD8 T cells can divide independently of IL-2 and elicit effector function in the absence of division (45). Therefore, IL-2-receptor blocking drugs that interfere with IL-2 responses of T cells may not inhibit the potent functions and expansion of memory T cells. However, other cytokines, such as IL-7 and IL-15, have been found to affect both memory CD4 and CD8 generation, homeostatic proliferation and/or survival (see (46), for a review). For memory CD8 T cells, IL-15 is required for their homeostatic proliferation in vivo (47,48), but appears dispensable for antigen-driven proliferation (49). While memory CD4 T cells do not require IL-15 for homeostasis, IL-7 appears important for memory CD4 T-cell generation and survival (50,51). These results suggest that interfering with responses to IL-7 and IL-15 may affect the generation, survival and/or homeostatic turnover of memory T cells in vivo.

Resistance of Memory T Cells to Tolerance Induction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

Induction of donor-specific immunologic tolerance remains the ultimate goal in transplantation. Over the past several decades, a great deal has been learned about the mechanisms regulating primary immune responses, including utilization of adhesion molecules, chemokines, costimulatory pathways, and signaling pathways. Based on this knowledge, numerous strategies have been developed in small animal models, which have resulted in significantly prolonged allograft survival or even tolerance induction (52,53). Costimulation blockade of the CD154/CD40 pathway in the presence of donor-specific transfusion (DST) has been remarkably successful in promoting permanent survival of heart and islet allografts (54). However, this same strategy is wholly ineffective if the recipient has been previously primed with donor-specific antigen (55). Likewise, infection with Leischmania major (13) or LCMV (56,57) has been shown to generate primed T cells specific for certain mouse haplotypes, and this cross-reactive, allospecific memory is also refractory to tolerance induction strategies using costimulation blockade. Similarly, a regimen of combined CD28/CD40L blockade in combination with donor bone marrow and nonmyelosuppressive conditioning results in donor-specific tolerance of C57/BL6 hosts to BALB/c skin grafts, which does not occur if the recipient has been previously infected with LCMV (14). These results indicate that alloreactive memory T cells can mount effective rejection responses in the absence of costimulation, consistent with in vitro results (58). It has been suggested that failure of costimulation-based tolerance induction strategies in large animals may be owing to the increased proportion of memory T cells in these hosts compared with young rodents housed in pathogen-free conditions (59); however, this idea has not yet been subject to experimental testing.

Additional evidence suggesting the refractory nature of memory T cells to tolerance induction strategies derives from studies on autoimmune type I diabetes. Transplantation of syngeneic islets into autoimmune diabetic NOD mice results in rapid destruction of islet grafts, characteristic of a secondary response (60,61), and referred to as recurrent autoimmunity. Numerous strategies shown to prevent primary disease in NOD mice are ineffective against recurrent autoimmunity in islet T-cell transplantation (62), where reactivation of memory T cells is likely to occur.

Despite their insensitivity to costimulation blockade in vivo, memory T cells are not inherently refractory to tolerance induction. For example, in vivo tolerization of antigen-specific mouse memory CD4 and CD8 T cells has been shown to occur following administration of high doses of intravenous soluble peptide antigen (63) or low-avidity agonist-altered peptide ligands (64). Crosspresentation of peptide antigens by resting APC can also induce tolerance of memory T cells (63). In addition, we have shown that memory T cells are not terminally differentiated, but rather can display functional flexibility and plasticity (65) and recently, it has been shown that memory CD8 T-cell responses to allografts can be inhibited by CD4+ CD25+ regulatory T cells in vivo (66). When taken together, these results suggest that memory T cells are amenable to functional modulation. Further studies elucidating the mechanisms of memory T-cell functional plasticity and modulation will be critical in the rational design of strategies to induce tolerance of allospecific memory T cells.

Potential roles for memory T cells in transplant rejection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

The enhanced functional properties and diversity of memory T cells discussed above suggest that memory T cells may potentially participate in early and late graft rejection by a number of different mechanisms, (see schematic in Figure 1). Because effector-memory T cells can recirculate in peripheral tissues, memory T cells may be rapidly recruited and initiate early responses directly at the graft site. These effector-memory T cells could immediately produce effector cytokines in situ that recruit additional immune cells for early graft tissue damage (Figure 1). Alloreactive central memory T cells in lymphoid tissue may also be activated early after graft rejection and subsequently migrate to the graft site (Figure 1). Over time, generation of alloreactive memory may occur even in the presence of immunosuppression, resulting in an eventual accumulation of allospecific memory T cells primed for initiating future rejection (Figure 1). Defining the role of each of these pathways in graft destruction by memory T cells in vivo is essential for understanding the pathogenesis of transplant rejection.

image

Figure 1. Schematic, showing potential roles of alloreactive memory T cells in both early and late allograft rejection. Yellow-shading indicates early events and blue-shading represents later or long-term events in graft rejection.

Download figure to PowerPoint

Future Strategies

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

Effective targeting of memory T cells requires further definition of the costimulatory pathways or cytokines that mediate memory T-cell homing and reactivation, the distinct signaling pathways that memory T cells utilize for their generation, activation and effector function, and an understanding of the diverse cellular subsets that comprise the memory T-cell pool. These aspects of memory T cells are currently active areas of investigation, and recent studies have begun to identify molecules and pathways preferentially used by memory T cells. For example, there is increasing evidence that costimulatory receptors belonging to the TNF receptor family may be important both for generation of long-lived memory and memory T-cell function (67). Indeed, combined blockade of the OX40-OX40L and CD28/B7 pathways significantly prolongs cardiac allograft survival in presensitized recipients (68). In addition, the CD28-related costimulatory molecule, inducible costimulator (ICOS), has been shown to costimulate both cytokine production and proliferation by memory CD4 T cells (69), suggesting that this molecule may also be a critical regulator in the reactivation of circulating memory T cells.

It may also be possible to specifically inhibit memory cells by targeting adhesion molecules up-regulated on the cell surface. In this regard, both LFA3-Ig (which binds to CD2) and anti-CD11a are effective against effector-memory T cells in the treatment of psoriasis (CD4+CD45RO+ and CD8+CD45RO+) (70,71). Other potential targets to inhibit recall responses include cytokines or chemokines (or their corresponding receptors) that control memory T-cell function, homeostasis and survival. Recently, blockade of the common cytokine receptor gamma chain (shared by cytokines IL-2, IL-4, IL-7, IL-15, and IL-21) has been shown to functionally inhibit autoreactive memory-like T cells in NOD mice (72), whereas CD28/CD154 blockade was ineffective (60). Defining the precise roles of memory T cells in graft rejection will enable the design of therapies tailored against specific recall functions.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

Specific dampening or tolerization of the T-cell arm of the immune response has been a major goal in transplantation. All of the currently implemented pharmacologic and immunologic protocols for prolonging graft survival both in the clinic and the laboratory have been designed and tested based on primary T-cell responses mediated by the activation of naive T cells. However, the T-cell compartment in all individuals comprises both naive and preprimed memory T cells, both with the potential to respond to alloantigen, and there is increasing evidence to suggest that most transplant recipients harbor alloantigen-specific memory T cells. The alloreactive memory T-cell response may impact on graft survival at both early and late times after transplant owing to their enhanced properties and diverse tissue distribution. We have discussed here how the robust effector responses and less stringent activation requirements of memory T cells may make them more difficult to turn off, how their broad homing properties may enable rapid responses at the graft site, and why incorporating memory T-cell blockade should be a critical consideration in the future design of strategies to induce transplant tolerance.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References

We wish to thank Dr Gregg A. Hadley and Dr Stephen T. Bartlett for critical reading of this manuscript. A.W.B. is supported by a grant from the Harry and Jeanette Weinberg Foundation, and D.L.F. is supported by NIH AI42092 and NIH AI50632.

References

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  2. Abstract
  3. Introduction
  4. Distinguishing Features of Memory T Cells
  5. Effect of Memory T Cells on Allograft Survival
  6. Resistance of Memory T Cells to Tolerance Induction
  7. Potential roles for memory T cells in transplant rejection
  8. Future Strategies
  9. Conclusions
  10. Acknowledgments
  11. References
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