Heterogeneity and Cell-Fate Decisions in Effector and Memory CD8+ T Cell Differentiation during Viral Infection
2007; Cell Press; Volume: 27; Issue: 3 Linguagem: Inglês
10.1016/j.immuni.2007.08.007
ISSN1097-4180
AutoresSusan M. Kaech, E. John Wherry,
Tópico(s)Immunotherapy and Immune Responses
ResumoHeterogeneity is a hallmark of the adaptive immune system. This is most evident in the enormous diversity of B and T cell antigen receptors. There is also heterogeneity within antiviral T cell populations, and subsets of effector and memory T cells now permeate our thinking about specialization of T cell responses to pathogens. It has been less clear, however, how heterogeneity in developing virus-specific effector and memory T cells is related to cell-fate decisions in the immune response, such as the generation long-lived memory T cells. Here we discuss recent findings that might help redefine how heterogeneity in antiviral T cell populations gives rise to T cell subsets with short- and long-lived cell fates. Heterogeneity is a hallmark of the adaptive immune system. This is most evident in the enormous diversity of B and T cell antigen receptors. There is also heterogeneity within antiviral T cell populations, and subsets of effector and memory T cells now permeate our thinking about specialization of T cell responses to pathogens. It has been less clear, however, how heterogeneity in developing virus-specific effector and memory T cells is related to cell-fate decisions in the immune response, such as the generation long-lived memory T cells. Here we discuss recent findings that might help redefine how heterogeneity in antiviral T cell populations gives rise to T cell subsets with short- and long-lived cell fates. Immunological Memory (IM) is a defining characteristic of the adaptive immune system that, during primary infection, produces long-lived plasma cells and memory T and B cells. These memory B and T cells are endowed with unique properties that permit more vigorous and specific responses upon reinfection to protect against pathogens. These key memory B and T cell properties are central to our current understanding of IM, yet the pathways that give rise to optimal memory B and T cells remain poorly understood. This review will focus principally on the development of memory T cells during viral infection. The accompanying review by Dörner and Radbruch covers recent work on antiviral B cell responses (Dörner and Radbruch, 2007Dörner T. Radbruch A. Antibodies and B cell memory in viral immunity.Immunity. 2007; 27 (this issue): 384-392Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Here we focus on recent advances in our understanding of antiviral memory CD8+ T cell differentiation and, although the majority of the discussion focuses on viral systems, selected data from nonviral experimental models are also discussed, where relevant to antiviral immunity. Over the last ten years, the innovation of major histocompatibility complex (MHC) class I and II tetramers, the use of T cell receptor (TCR) transgenic mice, and other techniques have led to the detailed quantitation, isolation, and characterization of virus-specific T cell populations in mice, nonhuman primates, and humans during infection. This work outlined the kinetics of virus-specific responses with great precision (Figure 1). A T cell response to a typical acute viral infection can be characterized by three distinct phases: expansion and effector T cell differentiation (profound clonal expansion and acquisition of effector functions), contraction (death of the majority of activated effectors T cells via apoptosis), and stable memory (formation of a numerically stable long-lived population of memory T cells) (Ahmed and Gray, 1996Ahmed R. Gray D. Immunological memory and protective immunity: Understanding their relation.Science. 1996; 272: 54-60Crossref PubMed Scopus (1441) Google Scholar, Williams and Bevan, 2007Williams M.A. Bevan M.J. Effector and memory CTL differentiation.Annu. Rev. Immunol. 2007; 25: 171-192Crossref PubMed Scopus (680) Google Scholar, Zinkernagel et al., 1996Zinkernagel R. Bachmann M. Kundig T. Oehen S. Pirchet H. Hengartner H. On Immunological Memory.Annu. Rev. Immunol. 1996; 14: 333-367Crossref PubMed Scopus (396) Google Scholar). Virus-specific T cells can expand as much as 104-fold to 105-fold, in as little as 8 days, from as few as 100–200 naive precursors (Arstila et al., 1999Arstila T.P. Casrouge A. Baron V. Even J. Kanellopoulos J. Kourilsky P. A direct estimate of the human alphabeta T cell receptor diversity.Science. 1999; 286: 958-961Crossref PubMed Scopus (690) Google Scholar, Blattman et al., 2002Blattman J.N. Antia R. Soudive D.J.D. Wang X. Kaech S.M. Murali-Krishan K. Altman J.D. Ahmed R. Estimating the precursor frequency of naive antigen-specific CD8 T cells.J. Exp. Med. 2002; 195: 657-664Crossref PubMed Scopus (466) Google Scholar). This massive T cell proliferation is critical to long-term immunity because the magnitude of the initial clonal burst typically determines memory T cell numbers (Hou et al., 1994Hou S. Hyland L. Ryan K. Portner A. Doherty P. Virus-specific CD 8+ T-cell memory determined by clonal burst size.Nature. 1994; 369: 652-654Crossref PubMed Scopus (470) Google Scholar, Murali-Krishna et al., 1998Murali-Krishna K. Altman J. Suresh M. Sourdive D. Zajac A. Miller J. Slansky J. Ahmed R. Counting antigen-specific CD8 T cells: A reevaluation of bystander activation during viral infection.Immunity. 1998; 8: 177-187Abstract Full Text Full Text PDF PubMed Scopus (1712) Google Scholar). Moreover, extensive cellular differentiation occurs as these newly activated T cells become potent antiviral effector T cells and ultimately memory T cells. Effector T cells migrate to virtually all tissues and eliminate the pathogen by killing infected cells, producing cytokines, and recruiting other leukocytes via chemokine production. In general, effector CD8+ T cells control infection through cytotoxic activity (via perforin and granzymes) and the secretion of interferon (IFN)-γ and tumor necrosis factor (TNF)α (Kaech et al., 2002bKaech S.M. Wherry E.J. Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development.Nat. Rev. Immunol. 2002; 2: 251-262Crossref PubMed Scopus (1313) Google Scholar, Wherry and Ahmed, 2004Wherry E.J. Ahmed R. Memory CD8 T-cell differentiation during viral infection.J. Virol. 2004; 78: 5535-5545Crossref PubMed Scopus (678) Google Scholar, Williams and Bevan, 2007Williams M.A. Bevan M.J. Effector and memory CTL differentiation.Annu. Rev. Immunol. 2007; 25: 171-192Crossref PubMed Scopus (680) Google Scholar). Effector CD4+ T cells take on a diverse set of roles and inhibit viral replication through the production of antiviral cytokines (and perhaps cytotoxicity), but they also activate dendritic cells (DCs) and provide help to B cells and CD8+ T cells (Seder and Ahmed, 2003Seder R.A. Ahmed R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation.Nat. Immunol. 2003; 4: 835-842Crossref PubMed Scopus (653) Google Scholar). After the expansion and contraction phases, a fraction (i.e., typically 5%–20%) of virus-specific T cells survives, forming a pool of memory T cells. Unlike most somatic cells in which terminal differentiation results in a functional, but a nonmitotic cell, the major product of memory T cell differentiation is a population of T cells that retains stem cell-like qualities. That is, after acute viral infections, long-lived memory T cells are endowed with multipotency, a high proliferative potential, telomerase expression, and self renewal (Williams and Bevan, 2007Williams M.A. Bevan M.J. Effector and memory CTL differentiation.Annu. Rev. Immunol. 2007; 25: 171-192Crossref PubMed Scopus (680) Google Scholar). These memory T cells persist in an antigen-independent, but cytokine-dependent (namely interleukin-15 [IL-15] and IL-7), manner, and slowly divide (referred to here as homeostatic turnover) (Surh et al., 2006Surh C.D. Boyman O. Purton J.F. Sprent J. Homeostasis of memory T cells.Immunol. Rev. 2006; 211: 154-163Crossref PubMed Scopus (239) Google Scholar). But almost immediately upon reinfection, memory T cells begin to produce effector molecules, undergo dramatic clonal expansion, and differentiate into secondary effector T cells. This qualitatively and quantitatively enhanced memory T cell response results in faster control of infection compared to a primary response (Figure 1). Thus, the cardinal features of memory T cells are maintenance of (1) high proliferative potential, (2) a multipotent state, meaning that memory T cells can maintain memory T cell identity but also rapidly reactivate antiviral effector functions upon reinfection, and (3) long-term survival and self renewal in the absence of antigen via IL-7- and IL-15-driven homeostatic turnover. This fairly customary description of effector and memory T cell differentiation during viral infection, however, does not incorporate the complexity of the multiple subpopulations of T cells that are now known to exist. These effector and memory T cell subsets differ not only in their effector functions, migratory properties, and proliferative potential, but also in their long-term persistence and ability to form protective memory T cells. How these distinct effector and memory T cell subsets form, function, and persist is a matter of great interest and will be the main topic of this review. Despite tremendous advances in our characterization of memory T cells in the last decade, we still do not know when and how memory T cells actually form after infection. The answers might largely depend on how one defines a memory T cell. One of the oldest but still most widely used definitions is based simply on time after infection; once antigen-specific T cell numbers stabilized (several weeks to months after infection), these cells were typically deemed memory T cells. However, this definition does not take into account the more concrete functional aspects and subsets of memory T cells described above. When considering the development of T cell memory on the basis of measurable memory T cell properties (i.e., high proliferative potential, multipotency, rapid recall, and homeostatic turnover), at least four possible models can be envisioned (Figure 2). Model 1—Uniform Potential. The first model is rooted in an extrinsic viewpoint. Here, the effector T cell pool is relatively homogenous, with each cell having acquired effector functions and memory T cell developmental potential equivalently. Competition for, or withdrawal from, nutrients, cytokines, growth factors, antigen, or other environmental resources limits the number of T cells that can survive contraction and enter the memory T cell pool (Freitas and Rocha, 2000Freitas A.A. Rocha B. Population biology of lymphocytes: The flight for survival.Annu. Rev. Immunol. 2000; 18: 83-111Crossref PubMed Scopus (379) Google Scholar). However, this simple model of memory T cell formation is insufficient to explain the heterogeneity within effector and memory T cell populations and also does not help define when memory T cell properties are acquired. Model 2—Decreasing Potential. In the second model, the early effector T cells also start off with relatively equal memory T cell developmental potential. However, the effector T cells progressively lose memory cell potential and are pushed toward terminal differentiation in a linear fashion as TCR stimulation is increased or prolonged (Ahmed and Gray, 1996Ahmed R. Gray D. Immunological memory and protective immunity: Understanding their relation.Science. 1996; 272: 54-60Crossref PubMed Scopus (1441) Google Scholar). This second model provides a mechanism for creating a heterogeneous pool of effector T cells in various stages of differentiation according to their stimulation history during infection. This model might be particularly useful in explaining the properties of latecomers in the T cell response (Catron et al., 2006Catron D.M. Rusch L.K. Hataye J. Itano A.A. Jenkins M.K. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells.J. Exp. Med. 2006; 203: 1045-1054Crossref PubMed Scopus (129) Google Scholar, D'Souza and Hedrick, 2006D'Souza W.N. Hedrick S.M. Cutting edge: Latecomer CD8 T cells are imprinted with a unique differentiation program.J. Immunol. 2006; 177: 777-781PubMed Google Scholar, Jelley-Gibbs et al., 2007Jelley-Gibbs D.M. Dibble J.P. Brown D.M. Strutt T.M. McKinstry K.K. Swain S.L. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response.J. Immunol. 2007; 178: 7563-7570PubMed Google Scholar) and T cell fates during chronic or latent infections or repetitive stimulation (Wherry and Ahmed, 2004Wherry E.J. Ahmed R. Memory CD8 T-cell differentiation during viral infection.J. Virol. 2004; 78: 5535-5545Crossref PubMed Scopus (678) Google Scholar). Although this model was originally based mostly on the effects of antigenic signaling, it does not rule out that exposure to other signals might be involved. Model 3—Fixed Lineage. A third model posits that memory or effector T cell lineage commitment occurs very early after the initial T cell stimulation, such that fully mature memory T cells and effector T cells coexist within the effector T cell population (Farber, 1998Farber D. Differential TCR signaling and the generation of memory T cells.J. Immunol. 1998; 160: 535-539PubMed Google Scholar, Sallusto and Lanzavecchia, 2001Sallusto F. Lanzavecchia A. Exploring pathways for memory T cell generation.J. Clin. Invest. 2001; 108: 805-806Crossref PubMed Scopus (84) Google Scholar). According to this model, these preformed memory T cells might bypass the effector stage, possess all characteristic traits of memory T cells, and survive the contraction phase, whereas the effector T cells die. Some evidence for this model is that at the peak of clonal expansion, a minority of T cells bears phenotypic resemblance to memory T cells found several weeks later (Lefrancois and Marzo, 2006Lefrancois L. Marzo A.L. The descent of memory T-cell subsets.Nat. Rev. Immunol. 2006; 6: 618-623Crossref PubMed Scopus (85) Google Scholar). Also, it is possible to isolate CD4+ T cells early in the immune response that do not have full effector function, but can persist long term (Wu et al., 2002Wu C.Y. Kirman J.R. Rotte M.J. Davey D.F. Perfetto S.P. Rhee E.G. Freidag B.L. Hill B.J. Douek D.C. Seder R.A. Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo.Nat. Immunol. 2002; 3: 852-858Crossref PubMed Scopus (244) Google Scholar). Furthermore, this model might more accurately portray the events that occur when naive T cells are primed under noninfectious conditions, such as with DC vaccines (Badovinac et al., 2005Badovinac V.P. Messingham K.A. Jabbari A. Haring J.S. Harty J.T. Accelerated CD8+ T-cell memory and prime-boost response after dendritic-cell vaccination.Nat. Med. 2005; 11: 748-756Crossref PubMed Scopus (331) Google Scholar). In another recent study, asymmetric separation of daughter cells at the first T cell division was observed, and one daughter T cell adopted a memory cell fate and the other an effector T cell fate (Chang et al., 2007Chang J.T. Palanivel V.R. Kinjyo I. Schambach F. Intlekofer A.M. Banerjee A. Longworth S.A. Vinup K.E. Mrass P. Oliaro J. et al.Asymmetric T lymphocyte division in the initiation of adaptive immune responses.Science. 2007; 315: 1687-1691Crossref PubMed Scopus (653) Google Scholar), suggesting that lineages might be fixed as early as the first cell division. It remains to be determined, though, how this 50:50 split in cell fates after division one leads to only 5%–20% of the clonal T cell burst entering the memory T cell pool. Model 4—Fate Commitment with Progressive Differentiation. The fourth model builds on the first three, but differs in several important respects. One distinction is that it postulates the existence of memory precursor effector cells (MPECs). These MPECs are not fully mature memory T cells, as in the third model, but rather they possess effector properties (hence MPEC) and require further differentiation to gain quintessential memory T cell properties, such as a high proliferative potential and the ability to undergo homeostatic turnover. Also, the effector T cell pool is heterogeneous and contains many short-lived effector cells (SLECs) that will die after infection, and a smaller fraction of MPECs with the potential to become long-lived memory T cells. The SLECs are a terminally differentiated cell population, but, unlike in the third model, the MPEC fate is not fixed. That is, the MPECs retain plasticity to develop into SLECs if additional strong stimulatory signals are encountered (e.g., persisting antigen and/or inflammation). This model is also consistent with early fate commitment in the first T cell division (Chang et al., 2007Chang J.T. Palanivel V.R. Kinjyo I. Schambach F. Intlekofer A.M. Banerjee A. Longworth S.A. Vinup K.E. Mrass P. Oliaro J. et al.Asymmetric T lymphocyte division in the initiation of adaptive immune responses.Science. 2007; 315: 1687-1691Crossref PubMed Scopus (653) Google Scholar) if the memory-fated daughter T cells require further differentiation events to mature into a long-lived memory T cell. In this model, the primary basis for the cell-fate decision is the magnitude of the overall strength of signal, which includes the combined effects of antigen, costimulation, and inflammation (signals 1, 2, and 3). High or excessively strong signals drive greater clonal expansion but also promote terminal effector T cell differentiation. The fourth model differs from the decreasing-potential hypothesis in that different cell fates can be specified early according to the intensity of the signals received (Gett et al., 2003Gett A.V. Sallusto F. Lanzavecchia A. Geginat J. T cell fitness determined by signal strength.Nat. Immunol. 2003; 4: 355-360Crossref PubMed Scopus (393) Google Scholar) but do not require multiple rounds of stimulation to create heterogeneous cell fates. Distinguishing which of the models of memory T cell development occurs during viral infections has been a difficult and controversial challenge. Indeed, these models are not mutually exclusive, and it is possible that multiple pathways exist for generating effector T cells and long-lived memory T cells depending on the T cell priming conditions. We will now discuss our current understanding of effector and memory T cell heterogeneity and the implications for T cell memory with these models as a guide. Initially, several reports suggested that the entire Naive → Effector → Memory (N → E → M) differentiation process could run on autopilot after a brief (∼24 hr) stimulation with antigen (Williams and Bevan, 2007Williams M.A. Bevan M.J. Effector and memory CTL differentiation.Annu. Rev. Immunol. 2007; 25: 171-192Crossref PubMed Scopus (680) Google Scholar). Subsequent work has shown that CD4+ T cell help, IL-2, inflammation, and persisting antigen can greatly influence memory T cell differentiation. Moreover, functional, phenotypic and gene-expression profiling of antigen-specific T cell populations during the course of an antiviral T cell response has led to the notion that fully competent memory T cells develop gradually after the clearance of acute viral infection (as referred to in models 1 and 4) (Kaech et al., 2002aKaech S.M. Hemby S. Kersh E. Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation.Cell. 2002; 111: 837-851Abstract Full Text Full Text PDF PubMed Scopus (768) Google Scholar). After most acute viral infections, the memory T cell pool slowly converts from a population containing mostly effector memory T (TEM) cells (e.g., CD62LLo, CCR7Lo, IL-2Lo) to one containing central memory T (TCM) cells (e.g., CD62LHi, CCR7Hi, IL-2+) that exhibit a high proliferative potential and can homeostatically turn over (Wherry and Ahmed, 2004Wherry E.J. Ahmed R. Memory CD8 T-cell differentiation during viral infection.J. Virol. 2004; 78: 5535-5545Crossref PubMed Scopus (678) Google Scholar). A number of other important phenotypic changes also occur gradually in the memory pool, resulting in memory T cells with a more mature phenotype (IL-7RHi, CD27Hi, CD122Hi, Bcl-2Hi, KLRG1Lo, CXCR3Hi, and CD43Lo) that differs considerably from the starting effector T cell population (Figure 3 and Table 1) (Badovinac et al., 2007Badovinac V.P. Haring J.S. Harty J.T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8(+) T cell response to infection.Immunity. 2007; 26: 827-841Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, Hikono et al., 2007Hikono H. Kohlmeier J.E. Takamura S. Wittmer S.T. Roberts A.D. Woodland D.L. Activation phenotype, rather than central- or effector-memory phenotype, predicts the recall efficacy of memory CD8+ T cells.J. Exp. Med. 2007; 204: 1625-1636Crossref PubMed Scopus (246) Google Scholar, Kaech et al., 2003Kaech S.M. Tan J.T. Wherry E.J. Konieczny B.T. Surh C.D. Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.Nat. Immunol. 2003; 4: 1191-1198Crossref PubMed Scopus (1436) Google Scholar, Wherry et al., 2004Wherry E.J. Barber D.L. Kaech S.M. Blattman J.N. Ahmed R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection.Proc. Natl. Acad. Sci. USA. 2004; 101: 16004-16009Crossref PubMed Scopus (413) Google Scholar, Wherry et al., 2003Wherry E.J. Teichgraber V. Becker T.C. Masopust D. Kaech S.M. Antia R. von Andrian U.H. Ahmed R. Lineage relationship and protective immunity of memory CD8 T cell subsets.Nat. Immunol. 2003; 4: 225-234Crossref PubMed Scopus (1470) Google Scholar). Because this process is gradual, a snapshot taken at one or two time points early after infection might be insufficient to appreciate the full dynamics and timeframe of these changes. The phenotypic changes in the memory T cell population could result from selective survival of different subsets (model 3), actual cellular conversion (models 1 and 4), or both.Table 1Characteristics of T Cells Responding to Different Types of Viral InfectionsType of InfectionPhenotype of T CellsFunctional PropertiesExamples of InfectionsAcute viral Infection (Memory Phase)CD62LHi > CD62LLo–High proliferative potentialLCMV (Acute Strains)CD44Hi–Potent effector functions (IFN-γ, TNF-α, IL-2, cytotoxicity)VSVCD27Int/Hi–Potent homeostatic turnoverVaccinia virusCD11aHi–Antigen-independent persistenceInfluenza virusCCR7HiRSVCD127HiSendai VirusCXCR3HiKLRG1LoCD122HiCD43LoPD-1LoCD69LoCD57LoLatent, Reactivating InfectionCD62LLo > CD62LHi–Intermediate proliferative potentialγHVCD44Hi–Weaker effector functions (lower IFN-γ, TNF-α, IL-2)EBVCD27Lo/Int–Reduced homeostatic turnoverCMVCD11aHiHSVCCR7Lo/HiCD127Lo/IntCD122LoKLRG1Hi/LoPD-1Int/HiCD69LoCD57HiChronic, Persistent InfectionCD62LLo–Low proliferative potentialLCMV (chronic strains)CD27Lo/Int–Poor effector functions (exhausted)HCVCD44Hi–Little or no homeostatic turnoverHIVCCR7Lo–Antigen-dependent persistenceSIVCD11aHiCD122Hi/LoCD127Lo/intPD-1HiKLRG1Hi/LoCD57HiCD69Hi Open table in a new tab The progressive changes in memory T cell function (e.g., high proliferative potential, homeostatic turnover) that accompany the E → M transition help to delineate when memory T cells form after acute infection. These data alone, however, do not distinguish whether the effector T cell population is homogenous or heterogeneous with regard to the potential to form memory T cells (model 1 versus models 2, 3, and 4). The examination of gene and surface marker expression has demonstrated that, like the memory T cell population, the effector T cell population is rich in cellular and functional heterogeneity (Wherry and Ahmed, 2004Wherry E.J. Ahmed R. Memory CD8 T-cell differentiation during viral infection.J. Virol. 2004; 78: 5535-5545Crossref PubMed Scopus (678) Google Scholar). In particular, a subset of effector CD8+ T cells can be identified that already expressed certain features of memory CD8+ T cells, such as increased IL-7R expression (Huster et al., 2004Huster K.M. Busch V. Schiemann M. Linkemann K. Kerksiek K.M. Wagner H. Busch D.H. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets.Proc. Natl. Acad. Sci. USA. 2004; 101: 5610-5615Crossref PubMed Scopus (386) Google Scholar, Kaech et al., 2003Kaech S.M. Tan J.T. Wherry E.J. Konieczny B.T. Surh C.D. Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.Nat. Immunol. 2003; 4: 1191-1198Crossref PubMed Scopus (1436) Google Scholar). However, these IL-7RHi effector CD8+ T cells did not appear to be preformed memory T cells (model 3), but rather they were more like MPECs (model 4). The IL-7RHi T cells had full effector function and expressed cytotoxic molecules (e.g., granzyme B) and IFN-γ, but, similar to their IL-7RLo counterparts, the IL-7RHi effector T cells had a relatively low proliferative capacity compared to mature memory T cells (Huster et al., 2004Huster K.M. Busch V. Schiemann M. Linkemann K. Kerksiek K.M. Wagner H. Busch D.H. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets.Proc. Natl. Acad. Sci. USA. 2004; 101: 5610-5615Crossref PubMed Scopus (386) Google Scholar, Kaech et al., 2003Kaech S.M. Tan J.T. Wherry E.J. Konieczny B.T. Surh C.D. Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.Nat. Immunol. 2003; 4: 1191-1198Crossref PubMed Scopus (1436) Google Scholar). The IL-7RHi effector T cells, however, had a substantially increased ability to become self-renewing memory T cells compared to the IL-7RLo effector T cells (Huster et al., 2004Huster K.M. Busch V. Schiemann M. Linkemann K. Kerksiek K.M. Wagner H. Busch D.H. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets.Proc. Natl. Acad. Sci. USA. 2004; 101: 5610-5615Crossref PubMed Scopus (386) Google Scholar, Kaech et al., 2003Kaech S.M. Tan J.T. Wherry E.J. Konieczny B.T. Surh C.D. Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.Nat. Immunol. 2003; 4: 1191-1198Crossref PubMed Scopus (1436) Google Scholar). A number of subsequent studies in infectious models support the idea that the IL-7RHi fraction of effector CD8+ T cells contains MPECs, though in some cases (e.g., low inflammatory conditions), not all IL-7RHi effector T cells are destined to populate the memory pool (Castellino and Germain, 2007Castellino F. Germain R.N. Chemokine-guided CD4+ T cell help enhances generation of IL-6RalphahighIL-7Ralpha high prememory CD8+ T cells.J. Immunol. 2007; 178: 778-787PubMed Google Scholar, Hand et al., 2007Hand T.W. Morre M. Kaech S.M. Expression of IL-7 receptor {alpha} is necessary but not sufficient for the formation of memory CD8 T cells during viral infection.Proc. Natl. Acad. Sci. USA. 2007; 104: 11730-11735Crossref PubMed Scopus (154) Google Scholar, Huster et al., 2004Huster K.M. Busch V. Schiemann M. Linkemann K. Kerksiek K.M. Wagner H. Busch D.H. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets.Proc. Natl. Acad. Sci. USA. 2004; 101: 5610-5615Crossref PubMed Scopus (386) Google Scholar, Kaech et al., 2003Kaech S.M. Tan J.T. Wherry E.J. Konieczny B.T. Surh C.D. Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.Nat. Immunol. 2003; 4: 1191-1198Crossref PubMed Scopus (1436) Google Scholar, Lacombe et al., 2005Lacombe M.H. Hardy M.P. Rooney J. Labrecque N. IL-7 receptor expression levels do not identify CD8+ memory T lymphocyte precursors following peptide immunization.J. Immunol. 2005; 175: 4400-4407PubMed Google Scholar). Taken together, it appears that by approximately 1 to 2 weeks after viral infection, effector CD8+ T cells have committed to short-lived or long-lived cell fates. What are the signals and genetic pathways that affect T cell longevity and specify different effector and memory T cell lineages? Although we are far from a complete understanding of these pathways, a substantial body of work has outlined some key factors, including (1) the role of CD4+ T cell help , (2) common gamma-chain cytokines, and (3) the strength of antigenic and inflammatory signals during T cell priming. CD4+ T cells, CD40-CD40L signals, and IL-2 help to maximize effector CD8+ T cell expansion, an effective E → M transition, and long-term maintenance after acute viral infections (Northrop and Shen, 2004Northrop J.K. Shen H. CD8+ T-cell memory: Only the good ones last.Curr. Opin. Immunol. 2004; 16: 451-455Crossref PubMed Scopus (45) Google Scholar, Rocha and Tanchot, 2004Rocha B. Tanchot C. Towards a cellular definition of CD8+ T-cell memory: The role of CD4+ T-cell help in CD8+ T-cell responses.Curr. Opin. Immunol. 2004; 16: 259-263Crossref PubMed Scopus (85) Google Scholar, Williams and Bevan, 2007Williams M.A. Bevan M.J. Effector and memory CTL differentiation.Annu. Rev. Immunol. 2007; 25: 171-192Crossref PubMed Scopus (680) Google Scholar). The result of defective CD4+ T cell help is the generation of a population of antiviral CD8+ T cells that largely resembles TEM cells, responds poorly to rechallenge, and in some cases expresses the death receptor, Trail (Badovinac et al., 2006Badovinac V.P. Messingham K.A. Griffith T.S. Harty J.T. TRAIL deficiency delays, but does not prevent, erosion in the quality of “helpless” memory CD8 T cells.J. Immunol. 2006; 177: 999-10
Referência(s)