REVIEW J Am Soc Nephrol 14: 2402–2410, 2003
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REVIEW J Am Soc Nephrol 14: 2402–2410, 2003 Memory T Cells: A Hurdle to Immunologic Tolerance FADI G. LAKKIS* and MOHAMED H. SAYEGH† *Section of Nephrology, Department of Internal Medicine, and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut; and †Renal Division, Brigham and Women’s Hospital, and Nephrology Division, Children’s Hospital, Harvard Medical School, Boston, Massachusetts. The induction of immunologic tolerance is an important Immunobiology of Memory T Cells clinical goal in transplantation and autoimmunity. Immuno- Upon exposure to a foreign antigen, antigen-specific T logic tolerance is traditionally defined as specific unrespon- cells proliferate (the expansion phase) and differentiate into siveness to a self- or foreign antigen while maintaining reac- effectors that eliminate the foreign intruder (Figure 1). The tivity to other (third party) antigens (1,2). In the context of vast majority of effector T cells, however, undergo apopto- transplantation, a tolerant patient is someone who is capable of sis as the immune response progresses (the death phase), mounting an effective immune response to vaccines and mi- and the few lymphocytes that survive become long-lived crobial pathogens but is incapable of rejecting the transplanted memory T cells (the memory phase) (8,9). Memory T cells organ. Similarly, induction of tolerance to an antigen that that recognize microbial antigens provide the organism with incites self-reactivity would ensure that the patient is free of long-lasting protection against potentially fatal infections. autoimmune manifestations in the absence of global and harm- Conversely, memory T cells that recognize donor alloanti- ful immunosuppression. Although several immunomodulatory gens jeopardize the survival of life-saving organ transplants strategies have been used successfully to induce immunologic by mediating rejection (10). Therefore, the central question in the pursuit of transplantation tolerance is how to coerce tolerance in rodents, the same strategies have failed in larger an immune response determined to generate T cell memory animals and in humans. Examples of induced tolerance in into a state of antigen-specific unresponsiveness. To begin organ transplant recipients or in patients with autoimmune to answer this question, we first highlight the general char- disease have been rare and often unintentional (3–6). acteristics of memory T cells that distinguish them from Why, then, has clinical tolerance been such an elusive goal? naïve T cells. Second, we summarize what is known about The answer to this question most likely lies in the immunologic the generation, maintenance, and activation (recall) of mem- barriers that preclude the induction of antigen-specific unre- ory T cells. sponsiveness in the adult animal (1,2). These barriers include the limitations of peripheral (extrathymic) immunoregulatory Memory Advantage mechanisms that are commonly exploited to induce tolerance Memory T cells have over their naïve counterparts several (T cell deletion, suppression, deviation, and anergy), the large inherent advantages that endow them with the ability to clear a repertoire of alloreactive T cells in the case of transplantation, foreign antigen, whether a microbial pathogen or an allograft, the uncertain nature of the pathogenic antigen in many auto- in a vigorous manner (Table 1). The first advantage that immune diseases, and the unavoidable fact that the adaptive memory T cells have is that their response to a foreign antigen immune response, by virtue of evolutionary design, is destined (recall response) is greater in magnitude and faster than the to generate immunologic memory. It is the last barrier that is naïve T cell response. Memory T cells generate a considerable perhaps the most important obstacle to immunologic tolerance. number of effector T cells, capable of cytokine secretion and/or Here, we address this thesis by reviewing the immunobiology cytolytic activity, within hours of antigenic restimulation, of memory T cells and their impact on solid organ transplan- whereas naïve T cells generate a smaller number of effectors tation. The same concepts that apply to understanding and and at a much slower pace (days) (11–14). Second, memory T controlling memory T cells in the context of transplantation are cells have a survival advantage over their naïve counterparts also relevant to autoimmunity (7). (15,16). Antigen-specific memory T cell populations persist for years to a lifetime in humans, and their survival seems to be antigen and MHC independent (17–19). Mature naïve T cell populations also persist for a relatively long period of time (months to a few years in humans), but their survival is Correspondence to Dr. Fadi G. Lakkis, Section of Nephrology, 333 Cedar Street, P.O. Box 208029, New Haven, CT 06520-8029. Phone: 203-737-2619; dependent on constant, low-grade stimulation with MHC–self- Fax: 203-737-1810; E-mail: [email protected] peptide complexes (20–22). Third, the circulation of naïve T 1046-6673/1409-2402 cells is restricted to secondary lymphoid tissues, the site where Journal of the American Society of Nephrology they are activated by foreign antigens presented by antigen- Copyright © 2003 by the American Society of Nephrology presenting cells (APC), whereas memory T cells circulate DOI: 10.1097/01.ASN.0000085020.78117.70 through both secondary lymphoid tissues and peripheral non- J Am Soc Nephrol 14: 2402–2410, 2003 Memory T Cells 2403 Figure 1. Foreign antigen triggers the proliferation of antigen-specific T cells (the expansion phase) and their differentiation into effectors. The vast majority of effector T cells undergo apoptosis (the death phase) as the foreign antigen is eliminated, and the few lymphocytes that survive become long-lived memory T cells (the memory phase). Immunologic tolerance can perhaps be viewed as the demise of antigen-specific memory lymphocytes or their precursors (red arrows). Table 1. Advantages of memory T cells over naı¨ve and effector T cellsa Characteristic Naı¨ve T Cell Effector T Cell Memory T Cell Survival Months to years Hours to days Years to lifetime Dependent on TCR Ag persistence leads Not dependent on TCR interaction with MHC/Ag to AICD interaction with MHC/Ag Migration Secondary lymphoid tissues Nonlymphoid tissues Both lymphoid and nonlymphoid tissues Response and effector Requires stimulation with Immediate Requires restimulation with function Ag Ag but is faster and larger in magnitude than naı¨ve T cells In vivo protection against Long-lived but relatively Short-lived but very Long-lived and efficient foreign Ag inefficient efficient a AICD, activation-induced cell death; Ag, antigen; TCR, T cell receptor for antigen. lymphoid tissues (23–25). Unlike naïve T cells, memory T pated. An antigen-experienced animal will eliminate the for- cells can directly encounter foreign antigen and mount a pro- eign antigen, whether a virus or an allograft, more efficiently ductive immune response within nonlymphoid tissues (25). than a naïve animal. The migratory advantage of memory T cells, therefore, allows them to detect and eliminate a foreign intruder long before it Generation of Memory T Cells reaches secondary lymphoid tissues. In summary, the activa- Antigenic stimulation of naïve T cells is a prerequisite for tion, survival, and migration advantages of memory T cells memory generation (26,27). It is also established that the confer the organism with enhanced protection against foreign magnitude of the expansion phase (burst size) of the primary antigens long after the primary immune response has dissi- immune response determines the size of the memory T cell 2404 Journal of the American Society of Nephrology J Am Soc Nephrol 14: 2402–2410, 2003 pool (28,29). Vaccination strategies that enhance T cell acti- naïve T cells that received suboptimal antigenic stimulation vation and proliferation by using strong adjuvants lead to larger and failed to proliferate. Importantly, it is not known how memory T cell populations. Because adjuvants directly influ- activated/effector T cells transition to the memory phenotype ence APC maturation and function, it is generally believed that (which is relatively quiescent and resembles that of a naïve T factors that stimulate the innate immune response, for example cell) and whether this transition is a stochastic process or an by inducing IFN-1 production or engaging Toll-like receptors instructional one (51). on APC (30,31), result in stronger adaptive immune responses Finally, recent studies propose the existence of two subsets and, subsequently, more memory T cells. Allografts are potent of CD4ϩ and CD8ϩ memory T cells based on the expression adjuvants as they contain their own APC and are subjected to of the homing receptors CC-chemokine receptor 7 (CCR7) and ischemia-reperfusion injury at the time of transplantation, L-selectin (CD62L) (56). The CCR7ϩ CD62Lhi “central” Ϫ lo which leads to activation of the innate immune system (32). In memory T cells (TCM) and CCR7 CD62L “effector” mem- fact, signaling via Toll-like receptors on graft dendritic cells ory T cells (TEM) have distinct migratory and functional char- plays an important role in initiating the alloimmune response acteristics (56–58). TCM circulate through secondary lymphoid ␥ (33). Therefore, it should not come as a surprise that transplant tissues, produce IL-2 but little IFN- and no perforin. TEM recipients harbor significant numbers of alloreactive memory T circulate through nonlymphoid peripheral tissues and produce and B cells. IFN-␥, perforin, and IL-4 but little IL-2. It has been proposed Because optimal T cell activation and proliferation require that the secondary lymphoid tissue resident TCM are responsi- the presence of adequate T cell co-stimulation, several co- ble for replenishing the memory T cell pool because of their stimulatory molecule pairs contribute to the generation of increased proliferative capacity, whereas the nonlymphoid tis- ϩ memory T cells. CD4 T cell proliferation and memory gen- sue resident TEM mediate effector functions and rapid elimi- eration are significantly impaired but not completely absent in nation of antigen (23,24,56).