Memory T Cells

Memory… is the diary that we all carry about with us. ∼Oscar Wilde, "The Importance of Being Earnest"And so it is with the immune system. Memory T cells are a critical component of the adaptive immune system. Our ability to respond rapidly to antigens/pathogens that we have been exposed to previously is at the heart of the adaptive immune system. In general, these memory T cells allow protection of the host to pathogens that the individual has previously encountered and/or been vaccinated against. The secondary response is rapid and more potent, leading to a rapid clearance of the offending agent. Not surprisingly, this population has also been explored in their contribution to graft-versus-host disease (GVHD).T Cells in Hematopoietic Cell TransplantationT cells have been clearly implicated in the pathogenesis of acute GVHD (aGVHD). There are extensive clinical data demonstrating that rigorous T cell depletion (TCD) abrogates aGVHD. Unfortunately, in many clinical settings, this process can result in loss of facilitation of engraftment as well as high incidence of relapses because of the loss of the graft-versus-tumor effect.The ability of the host to recover normal adaptive immunity is a centerpiece for successful allogeneic hematopoietic stem cell transplantation (HSCT). The recovery of normal T cells is a portion, albeit an important one, of normal immunity. The other cells are also important such as dendritic cells, B cells, monocytes, macrophages, and the recovery of the innate immune system. Recovery of normal numbers of T cells and normal function is governed by many factors such as the type of preparatory regimen, the status of the thymus and secondary lymphoid organs, homeostatic proliferation of donor and residual recipient T cells, regulation of T cell apoptosis, presence of harmful immunesuppressants such as calcineurin inhibitors or steroids, or possible beneficial immunesuppressants such as sirolimus.T Cell DevelopmentThe ontogeny of T cells and its T has been extensively studied [1Boyd R.L. Hugo P. Towards an integrated view of thymopoiesis.Immunol Today. 1991; 12: 71-79Abstract Full Text PDF PubMed Scopus (202) Google Scholar, 2Anderson G. Moore N.C. Owen J.J. Jenkinson E.J. Cellular interactions in thymocyte development.Annu Rev Immunol. 1996; 14: 73-99Crossref PubMed Scopus (429) Google Scholar, 3von Boehmer H. Fehling H.J. Structure and function of the pre-T cell receptor.Annu Rev Immunol. 1997; 15: 433-452Crossref PubMed Scopus (282) Google Scholar, 4Zuniga-Pflücker J.C. Lenardo M.J. Regulation of thymocyte development from immature progenitors.Curr Opin Immunol. 1996; 8: 215-224Crossref PubMed Scopus (150) Google Scholar]. T cells are generated from hematopoietic stem cells (HSC) found in the bone marrow. Common lymphoid progenitors give rise to T cell precursors or immature thymocytes. These cells populate the thymus initially as double negative cells (CD4−CD8−). As these cells mature, they become double positive (CD4+CD8+) before becoming mature T cells that are single positive (CD4+ or CD8+). These single positive cells then egress from the thymus into the peripheral circulation.The majority of the immature thymocytes actually never leave the thymus. There is an intricate tightly regulated 2-step selection process that determines which T cells will be found in the circulation [5Sebzda E. Mariathasan S. Ohteki T. et al.Selection of the T cell repertoire.Annu Rev Immunol. 1999; 17: 829-874Crossref PubMed Scopus (416) Google Scholar]. The first step is termed positive selection. Here in the cortex of the thymus, the double positive T cells that can bind self-antigens in the context of the appropriate major histocompatibility complex (MHC) of the host's thymic epithelial cells are given a survival signal. Those cells that bind MHC class II molecules become single positive CD4+ cells, whereas those that bind MHC class I will become single positive CD8+ cells. All the other T cells that are not able to bind self-antigens undergo apoptotic cell death.This first step is fraught with the danger of engendering autoimmune T cells because each of the positively selected T cell can recognize self-antigens. Thus, a second equally negative selection step needs to occur. In this process, the positively selected thymocytes move to the medulla where they are presented with self-antigens in the context of the appropriate MHC by professional antigen-presenting cells (APCs) such as dendritic cells or macrophages. Those cells that bind with too high affinity to self-antigens are given a signal to undergo apoptosis. This process ensures that the majority of the highly autoreactive T cells do not slip into the peripheral blood where they may wreck havoc by causing an autoimmune process. During this process, a small number of T cells become regulatory T cells as well.Naïve Versus Memory T CellsT cells that have undergone positive and negative selection egress from the thymus into the circulation. These cells will circulate sampling antigens presented in the context of their respective MHC molecules. Naïve cells are fully mature T cells, but have not yet encountered the appropriate antigen that its T cell receptor can recognize. Naïve T cells express L-selectin (CD62L) and lack or have low expression of CD44 and activation markers such as CD25 and CD69. They also do not have any of the edited isoforms of CD45 (they are CD45RA versus memory T cells are CD45RO or RB). Naïve cells are thought to be relatively quiescent and do not divide until they encounter their antigen. They require IL-7 and IL-15 for homeostatic survival.Naïve T cells remain in this quiescent stage until they encounter the specific antigen to which its T cell receptor is targeted. The recognition of its cognate antigen triggers the naïve T cell to respond. If secondary signals in the form of costimulatory molecules occurs, that cell initiates the adaptive immune response. The naïve T cells produce IL-2, proliferate, and acquire an activated phenotype (CD25+, CD44+, CD69+) with a drop in the expression of L-selectin (CD62Llow). This response may occur in a CD4+ cell leading to a helper T cell response or in a CD8+ cell leading to a cytotoxic response.Encounter with the specific antigen drives a significant proliferation of the specific T cell clones to respond against the antigen. For example, if a patient develops influenza for the first time, then the specific naïve T cells for the immunodominant influenza peptides will proliferate. The CD4+ helper T cells produce cytokines and the cytotoxic CD8+ cells will destroy cells infected with the influenza virus and rid the host of the infection. In this process, many of these antigen specific cells will undergo apoptosis. As the infection dies down (ie, there is a drop off in the amount of influenza specific antigen), some of the antigen specific cells will become memory T cells, whereas others will become regulatory T cells, thus decreasing the nflammatory immune response.Memory T cells are those lymphocytes that have encountered antigen and mounted a response against such an antigen and thus are no longer antigen naïve [6Ochsenbein A.F. Pinschewer D.D. Sierro S. Horvath E. Hengartner H. Zinkernagel R.M. Protective long-term antibody memory by antigen-driven and T help-dependent differentiation of long-lived memory B cells to short-lived plasma cells independent of secondary lymphoid organs.Proc Natl Acad Sci USA. 2000; 97: 13263-13268Crossref PubMed Scopus (172) Google Scholar]. These cells are also normally in a quiescent state. If they encounter the same specific antigen, for example the same influenza virus, they will produce a rapid and robust immune response characterized by prompt proliferation, production of inflammatory cytokines and rapid clearance of the virus.There are at least 3 populations of CD8+ memory T cells and probably similar CD4+ cells. Broadly speaking, they are central versus effector memory T cells [7Sallusto F. Lenig D. Forster R. Lipp M. Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.Nature. 1999; 401: 708-712Crossref PubMed Scopus (4559) Google Scholar]. Central memory T cells are thought of as memory "stem cells." These cells tend to be long lived and carry the essential imprint of previous antigen exposure. These cells are thought to give rise to long-lived immunologic memory. The cells express L-selectin (CD62L+) and the chemokine receptor CCR7. They secrete IL-2 but not IL-4 or interferon-gamma.Effector memory T cells tend to express molecules with cytotoxic function. These effector memory cells (TEM or TEMRA) tend to produce cytokines such as interferon-gamma and IL-4. The TEM cells do not express CD62L or CCR7. Although CD45RA isoforms have been used to differentiate naïve (CD45RA) from memory T cells (CD45RO), some of the memory T cells will revert back to CD45RA and thus this marker alone is not absolute.Memory T Cells and Prevention of GVHDAs mentioned above, T cell depletion (TCD), whereas effective, can be associated with higher incidence of infection, lack of engraftment and relapse. There have been many attempts to parse the T cell subsets in different manners to overcome some of the concerns regarding these 3 complications. Examples of these include use of CD4, CD8, CD6, CD25, and CD69 positive or negative selection process for the initial graft as well as use of such markers for donor lymphocyte infusions. Some of these approaches remain promising in early trials. One other method could be to parse T cells into a memory versus a naïve phenotype to ascertain whether there is a difference in the incidence of GVHD based on these 2 broad T cell populations. What follows later from the summaries of Drs. Shlomchik and Chen are our current understanding of the contributions of the population of naïve versus memory T cells in aGVHD models and in human mixed lymphocyte cultures. It is hoped that such approaches will allow the beginnings of engineering a graft that contains most of the positive cellular components without the allospecific GVHD inducing cells.Memory T Cells in GVHD and GVLBritt E. Anderson,1 Hong Zheng,2 Patricia A. Taylor,3 Catherine Matte-Martone,4 Jennifer M. McNiff,5 Dhanpat Jain,6 Anthony J. Demetris,7 Angela Panoskaltsis-Mortari,3 Ann Ager,8 Bruce R. Blazar,3 Mark J. Shlomchik,9 Warren D. Shlomchik101Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut; 2Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; 3Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota; 4Section of Medical Oncology, Cancer Center, Yale University School of Medicine, New Haven, Connecticut; 5Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut; 6Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; 7Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 8Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, UK; 9Departments of Laboratory Medicine and Immunobiology, Yale University School of Medicine, New Haven, Connecticut; 10Section of Medical Oncology, Cancer Center and Department of Immunobiology, Yale University School of Medicine, New Haven, ConnecticutWe and others have recently shown that TEM do not cause graft-versus-host disease (GVHD) in MHC-matched and MHC-mismatched mouse strain pairings [1-4]. Yet, after transfer, memory T cells can mount an appropriate recall response in the recipient. However, there is no a priori reason to suppose that the essential features of memory phenotype cells will be different, even if a larger component of mouse cells with this phenotype arose by homeostatic proliferation [5,6].We have been avidly investigating why CD44+CD62 ligand (CD62L)−TEM do not mediate GVHD. At least 3 nonexclusive hypotheses could explain this finding. First, TEM may not traffic sufficiently to lymph nodes (LN) and Peyer's patches (PP) because of reduced expression of CD62L (also known as L-selectin) and/or CC-chemokine receptor 7 (CCR7). Implicit in this idea is that these are required sites for priming of TN. Second, TEM may have a more restricted TCR repertoire that reduces the frequency of alloreactive T cells below the threshold necessary to induce GVHD. That TEM fail to induce GVHD in MHC-mismatched models, in which the overall frequency of alloreactive T cells among TN is as high as 10%, makes this unlikely to be the only explanation, although this hypothesis has not been fully excluded. Also, as TEM can mediate graft-versus-leukemia (GVL) (see below) and respond in mixed lymphocyte reactions against allogeneic stimulators indicates that alloreactive cells are present among TEM. Third, intrinsic properties of TEM— for example, reduced clonal expansion—could prevent the development of the complete GVHD syndrome [4].We have addressed the trafficking hypothesis in some detail. To do so we used T cells deficient in CD62L or CCR7, transplant recipients lacking PNAd ligands for CD62L, and recipients without LN, PP, or LN, PP, and spleen. Surprisingly, functional CD62L and CCR7 were not required for TN-mediated GVHD. Indeed, CCR7−/− T cells induced GVHD in recipients lacking PNAd ligands. We hypothesized that CD62L−/− T cells might have been primed in the spleen; however, CD62L−/− T cells induced GVHD in splenectomized recipients. In multiple strain pairings GVHD developed in recipients that lacked LN and PP. Mild GVHD could even be induced in mice lacking all major secondary lymphoid tissues (SLT). We unexpectedly observed in several cases that altering the trafficking and priming site of donor T cells affected the nature of GVHD. This phenomenon manifested both when priming occurred in the absence of the spleen or the PP/LN. In 3 MHC-mismatched models, LN/PP-intact but splenectomized recipients developed more rapidly lethal GVHD than WT (spleen intact) recipients. In the 129 → B6 MHC-matched model, the lack of LN/PP promoted the development of cutaneous GVHD. Conversely, enforced constitutive expression of CD62L on TEM did not endow them with the ability to cause GVHD. Taken together, these data argue against the hypothesis that TEM fail to induce GVHD because of inefficient trafficking to LN and PP. Moreover, these data indicate that no specific site of priming is essential for GVHD induction, although the GVHD phenotype can be altered in the absence of individual SLTs.We have also investigated whether CD4+ TEM, unprimed to recipient antigens, mediate GVL. We performed these experiments in an the MHCII-mismatched B6bm12×B6 strain pairing to parallel the dominant form of allorecognition in haploidentical alloSCT. CD4+ TEM mediated GVL against mouse models of chronic phase and blast crisis chronic myelogenous leukemia (without causing GVHD), although they were less potent inducers of GVL than were TN. By creating gene-deficient leukemias and using perforin-deficient T cells we found that direct cytolytic function is essential for TEM-mediated GVL, but that GVL is retained when killing via FasL, TNF-α, TRAIL, and perforin are individually impaired. However, TEM-mediated GVL was diminished when both FasL and perforin pathways were blocked. In sum, these results suggest that TEM retain sufficient cytolytic function to mediate GVL but lack other properties (eg., sufficient clonal expansion) required to establish GVHD.REFERENCES1. Anderson BE, McNiff J, Yan J, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. 2003;112:101-108.2. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood. 2004;103:1534-1541.3. Zhang Y, Joe G, Zhu J, et al. Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood. 2004;103:3970-3978.4. Beilhack A, Schulz S, Baker J, et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood. 2005;106:1113-1122.5. Hamilton SE, Wolkers MC, Schoenberger SP, Jameson SC. The generation of protective memory-like CD8+ T cells during homeostatic proliferation requires CD4+ T cells. Nat Immunol. 2006;7:475-481.6. Min B, Foucras G, Meier-Schellersheim M, Paul WE. Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc Natl Acad Sci USA. 2004;101:3874-3879.Allogeneic Memory T Cell ResponseBenny J. ChenDivision of Cellular Therapy/BMT, Duke University Medical Center, Durham, North CarolinaOne of the central features of the immune system is the ability to maintain memory after exposure to antigen [1-3]. However, results from several independent studies published in the past several years suggest that memory T cells do not cause graft-versus-host disease (GVHD) [4-8]. These results have also led investigators to study further the ability of allospecific memory T cells to induce GVHD [9-12]. In this review, we describe the ability of nonalloreactive, crossreactive, and allospecific memory T cells to induce GVHD and how these new concepts can be applied in allogeneic hematopoietic cell transplantation.NONALLOREACTIVE MEMORY T CELLSThe specificity of a memory T cell is determined by the T cell receptor that is produced by random gene rearrangement in thymus before it encounters the specific antigen [13]. Because naïve and memory T cells are exclusive T cell subsets, memory T cell subset should not contain host-antigen-specific T cells and should not be able to induce GVHD if the donor has not encountered antigens present in the host. Our group has further demonstrated that, similar to effector memory T cells, central memory T cells are unable to induce GVHD. GVHD-inducing T cells are exclusively contained in naïve phenotype T cells [8]. Because most of the memory T cells if not all are nonalloreactive in unprimed the data that nonalloreactive T cells do not induce MEMORY T it is from the studies that memory T cells from unprimed do not contain allospecific T cells and do not cause GVHD concerns about the of GVHD when this is into because the of but T cells These T cells could be activated by different antigens and with a of different or different Thus, the induced by these cells will different Because of it be to how different memory T cells to in However, there is to suggest that memory T cells also have ability to induce GVHD [8]. memory T cells do in unprimed because IL-2 production was in memory T cells with the low proliferation and as by the but these memory T cells that are to host antigens are unable to cause GVHD. Although the reason why these T cells induce GVHD has not been it is known that the mediated by these memory T cells be in mixed lymphocyte MEMORY T of selection of memory T cells is the of allospecific memory T cells in some memory T cells can be generated after exposure to in the form of blood or allospecific memory T cells mediate and immune response than naïve T cells In results from 2 different suggest that allospecific memory T cells have ability to induce GVHD with naïve T cells To allospecific memory T cells, we first primed the donor mice with host than we T cells from spleen and them into naïve and memory T cells subsets based on their expression of The results that from primed which mediate in have ability to mediate GVHD with cells from the same In to unprimed T cells from primed donor are able to induce GVHD. results have also been presented by et al. It is important to that these data are to the data published by Zhang et al. This group has demonstrated that allospecific memory T cells from GVHD mice have ability to induce GVHD with naïve T cells. It is why allospecific memory T cells from and from GVHD mice have different ability to induce GVHD. Because all the current models a population of memory T cells in which allospecific memory T cells only a small subset of T cells, a system such as those using allospecific T cell repertoire T cells may be to this more MEMORY T from T cell depletion (TCD) studies indicate that the of any for and of GVHD is not only to prevent but also to the beneficial mediated by T cells such as the as well as the of memory T cells on immune stem cell and be important to development of clinical cell cell transplantation peripheral of mature T cells contained in the graft and/or We and others have demonstrated that effector memory T cells can to T cell recovery We have further demonstrated that memory T cells from unprimed the generation of new T cells from cells These have that memory T cells to T cell not only peripheral but also These important suggest that memory T cells are of the stem cell recipients from early after transplantation by recall immunity and later by more T cell memory T cells are to some early protection but because they can induce also observed that host T cells were in memory T cell recipients but not in the T bone mice that memory T cells may be able to donor stem cell engraftment by host immune The that memory T cells are able to respond initially but fail to maintain the response (see for may explain why memory T cells are able to host cells without causing GVHD. this of memory T cells is by memory T cells in response to studies are required to this results from proliferation suggest that, similar to the response against unprimed memory T response to antigens is also in vivo experiments have demonstrated that unprimed memory T cells do have direct we have not the response by using in vivo the mediated by unprimed memory T cells is unlikely as as that mediated by naïve T cells, because similar may for the depletion of host cells and the of and these same T cells do not induce GVHD. by memory T cells could be by a donor carry memory T cells or after of the donor in vivo or Because memory T cells immune both peripheral and could also be hematopoietic cell from studies have that both nonalloreactive T cells and T cells do not induce GVHD and allospecific T cells cause less GVHD The major in using memory T cells be T cells, although in suggest that human memory T cells can but against clinical will be to whether this can be applied in to prevent GVHD. The of GVHD might but should not be higher with of T data have in mediated by memory T cells during and reactions in the are not it is that all memory T cells crossreactive, and allospecific memory T cells have ability to induce GVHD. of memory T cells or of naïve T cells will not only prevent but could also immune and have the to clinical has been of this in the will the the and the of allogeneic hematopoietic stem cell in Memory T Cell during and no with or without normal response. in a new J. New and S, The cellular of in The nature of memory cells mediating second heart graft J G, S, M, Immunol. Chen BJ, Cui Sempowski GD, Liu Chao NJ. Transfer of allogeneic memory T cells without graft-versus-host disease. Blood. Anderson BE, McNiff J, Yan J, et al. Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest. Zhang Y, Joe G, Zhu J, et al. Dendritic cell-activated CD44hiCD8+ T cells are defective in mediating acute graft-versus-host disease but retain graft-versus-leukemia activity. Blood. A. CD4 T lymphocytes for acute and chronic graft-versus-host disease are contained the but not the J Immunol. Chen BJ, Cui X, et al. of memory T cells to induce graft-versus-host disease is a result of an Blood. Chen BJ, Cui X, Chao NJ. memory T lymphocytes alone do not induce more graft-versus-host disease. Marrow S, J, et al. Memory CD4 T cells induce graft versus host disease. Blood. Zhang Y, Joe G, Zhu J, memory T cells are for the of graft-versus-host disease. J Immunol. Zhang Y, Joe G, Zhu J, memory stem cells in graft-versus-host disease. Nat G. The Sci S, et al. frequency of lymphocytes is a of immunologic memory and with the of J Immunol. Memory T cells in and in J The and of T-cell depletion as graft-versus-host disease for allogeneic hematopoietic stem cell Blood. of T-cell in mice and for bone transplantation and Anderson BE, Shlomchik Shlomchik Spontaneous memory T cells graft-versus-leukemia without causing graft-versus-host disease. Blood. Chen BJ, Cui X, J, Chao NJ. memory T cells new T cell from