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• W2057896643 abstract "T cell homeostasis must be tightly controlled. In this issue of Immunity, Cho et al., 2010Cho J.-H. Kim H.-O. Surh C.D. Sprent J. Immunity. 2010; 32 (this issue): 214-226Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar describe results that begin to define the roles of the T cell receptor, self-peptide-MHC ligands, cytokines, and membrane rafts in this dynamic process. T cell homeostasis must be tightly controlled. In this issue of Immunity, Cho et al., 2010Cho J.-H. Kim H.-O. Surh C.D. Sprent J. Immunity. 2010; 32 (this issue): 214-226Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar describe results that begin to define the roles of the T cell receptor, self-peptide-MHC ligands, cytokines, and membrane rafts in this dynamic process. In the past few years, there have been increasing efforts to understand all aspects of how a T cell receptor (TCR) influences many different biological activities of T cells. The TCR has long been known to control the primary function of T cells, that being recognition and elimination of antigen, but it is now clear that TCRs are also involved in the daily maintenance of T cells in the periphery. The structural side of immunology has focused attention on how a single TCR can cross-react with many different peptide-MHC (pMHC) ligands (Yin and Mariuzza, 2009Yin Y. Mariuzza R.A. Immunity. 2009; 31: 849-851Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar). On the cellular side, efforts have concentrated on describing the specific self-pMHC ligands that are recognized by a particular T cell (Wucherpfennig and Gagnon, 2009Wucherpfennig K.W. Gagnon E. Nat. Immunol. 2009; 10: 1143-1144Crossref PubMed Scopus (5) Google Scholar) and understanding the necessity for these interactions during the life of a T cell in the periphery. TCR:self-pMHC interactions are required for a T cell to survive in the periphery and to undergo homeostatic proliferation, as occurs in the lymphopenic state. In this issue of Immunity, Cho et al., 2010Cho J.-H. Kim H.-O. Surh C.D. Sprent J. Immunity. 2010; 32 (this issue): 214-226Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar put us one step closer to understanding the key mechanisms involved in the cellular process of T cell homeostasis. Cho et al. begin by showing that naive peripheral CD8+ T cells, but not CD4+ T cells, can proliferate when exposed to IL-2 or IL-15, even in the apparent absence of an agonist for the TCR. This result may seem contradictory to what we have learned, that T cells require signals through the TCR and other molecules such as CD28 for mature T cell activation. However, the study proceeds to show that these CD8+ T cells actually are receiving signals via their TCRs, through interactions with self-pMHC. This conclusion was reached by studying naive T cells derived from normal C57 mice and various TCR transgenic mice, together with antigen-presenting cells with deficiencies in MHC-I or the peptide transporter Tap1. In each case, IL-2 responsiveness was greatly reduced in the absence of MHC-I. What are the qualities of TCR interactions with self-pMHC that provide signals through certain TCRs, but not others? In this report by Cho et al. and elsewhere, a hierarchy of TCRs has been described based on the propensity of transgenic T cells carrying those receptors to proliferate in response to lymphopenia (e.g., OT-1 > 2C > HY; OT-1 > P14 > HY). These TCRs are specific for different agonist pMHC: OT-1 for OVA/Kb, 2C for SIY/Kb and p2Ca/Ld, P14 for viral peptide gp33/Db, and HY for the endogenous male antigen HY/Db. This propensity for homeostatic proliferation has been attributed to a putative distribution of affinities for self-pMHC, from high to low for the OT-1, P14/2C, and HY TCR transgenic systems, respectively. This observed hierarchy is based entirely on biological read-outs, where T cells are exposed to antigen-presenting cells that express an array of endogenous pMHC. There are no binding measurements for these interactions, and in fact, only a couple of self-peptides have been incriminated as putative ligands (e.g., Cappa192–99 for OT-1 and dEV8 for 2C [Santori et al., 2002Santori F.R. Kieper W.C. Brown S.M. Lu Y. Neubert T.A. Johnson K.L. Naylor S. Vukmanović S. Hogquist K.A. Jameson S.C. Immunity. 2002; 17: 131-142Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]). Because there are no data about the actual TCR:self-pMHC affinities involved, or indeed even about how many self-pMHC could serve as ligands for a given TCR, the processes that arise from TCR:self pMHC interactions cannot distinguish several possible scenarios, each of which could explain the hierarchies that are associated with activities of the different TCRs. Thus, increased TCR reactivity with self-pMHC could be due to (1) higher affinity for a single self pMHC ligand, (2) a higher density of a single self-pMHC ligand, (3) greater cross-reactivity with a large number of different self pMHC-ligands, or (4) a combination of these binding properties. The various transgenic TCRs could even bind to self peptides restricted by MHC alleles other than the allele associated with agonist. In the absence of any data to distinguish these possibilities, we refer to the interactions of a TCR with pMHC as “reactivities” rather than “affinities” (Figure 1). It is also worth pointing out that even good agonists can have very weak binding affinities (KD values as high as 300 μM have been described in a number of studies), and thus, it is likely that the affinities involved in self-pMHC reactions will actually be below those that can be measured by current techniques. Regardless of the mechanism of self-pMHC binding by the different transgenic TCRs, T cells with higher reactivity for self-pMHC were more sensitive to IL-2 and IL-15 than T cells with lower reactivity for self-pMHC. Cho et al. examined several key features that point to a plausible mechanism. GM1, a marker for lipid enriched rafts, was upregulated on the most self-reactive T cells and was directly correlated with sensitivity to IL-2. The important role of lipid rafts was supported by experiments in which the compound methyl-β-cyclodextrin, which disrupts rafts, inhibited IL-2 responsiveness. Furthermore, the IL-2 receptor β (IL-2Rβ) was found to colocalize with high-density patches of GM1. These findings suggested that the pathway that leads from binding of self-pMHC by TCRs to IL-2 responsiveness involves the enhanced generation of rafts that contain IL-2Rβ (Figure 1). As described by Cho et al., physiologically, this process might result in enhanced sensitivity to IL-15 or IL-7 (perhaps in combination with IL-12, which was also shown to synergize with IL-7 in stimulation of proliferation). Enhanced responsiveness to IL-2 in naive CD8+ T cells was also associated with higher expression of CD5, a negative regulator of TCR signaling (Tarakhovsky et al., 1995Tarakhovsky A. Kanner S.B. Hombach J. Ledbetter J.A. Müller W. Killeen N. Rajewsky K. Science. 1995; 269: 535-537Crossref PubMed Scopus (343) Google Scholar) that appears to reduce activation responses via recruitment of the phosphatase SHP-1. Increased expression of CD5 on more self-reactive T cells might make sense, as this would provide a mechanism for dampening a potential autoreactive pathology. However, the association of cytokine responsiveness with CD5 expression was not strictly correlative, as CD4+ T cells (which were nonresponsive to cytokines) had high expression of CD5. Hence, CD5 may indeed be controlling some activity of T cells with the most self-reactive TCRs, but it does not appear to be directly, or solely, responsible for enhanced IL-2 sensitivity. The role of coreceptor in this process is undoubtedly important for the T cell response to self pMHC, perhaps providing the key feature that distinguishes the cytokine responsiveness of CD8+ T cells from the nonresponsiveness of CD4+ T cells. It is quite likely that CD8 is required for both synergistic binding of these low-affinity self-pMHC-I ligands and for signaling that ultimately leads to cytokine responsiveness. By contrast, CD4 is thought to contribute less energy to class II pMHC binding, which may in part account for reduced reactivity with self pMHC. Furthermore, because the MHC II ligand for CD4+ T cells is only expressed on professional antigen-presenting cells, whereas the ligand for CD8+ T cells (MHC I) is expressed on all nucleated cells, it stands to reason that the frequency of TCR:self-pMHC II interactions in the periphery is far lower than TCR:self-pMHC I; these continual interactions may allow CD8+ T cells, rather than CD4+ T cells, to maintain increased sensitivity to cytokine. Although the behavior of CD4+ T cells in responses to self-pMHC has been studied more extensively (e.g., Wong et al., 2001Wong P. Barton G.M. Forbush K.A. Rudensky A.Y. J. Exp. Med. 2001; 193: 1179-1187Crossref PubMed Scopus (96) Google Scholar, Wucherpfennig and Gagnon, 2009Wucherpfennig K.W. Gagnon E. Nat. Immunol. 2009; 10: 1143-1144Crossref PubMed Scopus (5) Google Scholar), the contribution of self pMHC to recognition by CD8+ T cells has gained some ground (e.g., Yachi et al., 2005Yachi P.P. Ampudia J. Gascoigne N.R. Zal T. Nat. Immunol. 2005; 6: 785-792Crossref PubMed Scopus (111) Google Scholar; also see Krogsgaard et al., 2007Krogsgaard M. Juang J. Davis M.M. Semin. Immunol. 2007; 19: 236-244Crossref PubMed Scopus (40) Google Scholar for review of CD4 and CD8 cells). The study by Cho et al. provides yet additional evidence that not all peripheral CD8+ T cells are equal. Support has continued to mount to show that T cells can use various mechanisms to “tune” the sensitivities of TCR-mediated signaling (Dustin, 2009Dustin M.L. Immunity. 2009; 30: 482-492Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). These mechanisms include modified expression levels of important molecules, such as the TCR complex or CD8, altered glycosylation states of surface molecules, or localization of molecules to organized lipid microclusters or domains (as seen in Cho et al. for the IL-2Rβ and elsewhere for CD4 and CD8). Most studies have illustrated these principles using stimulation by agonist ligands. It will be interesting to now see how TCR binding to self-pMHC influences these and other properties. Additional issues that remain to be addressed include details regarding the specific self pMHC ligands for a particular T cell, the role of CD5 in light of its higher levels on the most IL-2-sensitive CD8 cells, and further information about the molecular links between TCR, CD3, CD8 signaling, and cytokine responsiveness. Finally, it should also be pointed out that these findings have some relevance to adoptive T cell therapies (Schmitt et al., 2009Schmitt T.M. Ragnarsson G.B. Greenberg P.D. Hum. Gene Ther. 2009; (in press. Published online October 1, 2009)https://doi.org/10.1089/hum.2009.146Crossref Scopus (70) Google Scholar). For example, efforts to transfer T cells that are transduced with a TCR that is specific for tumor-associated antigen will need to consider whether the TCR will be capable of mediating homeostatic processes in the recipient. Assuming that these findings extend to the human system, this work reveals possible strategies to test the transduced T cells for in vitro surrogate markers that predict their capacity to undergo homeostatic proliferation. T Cell Receptor-Dependent Regulation of Lipid Rafts Controls Naive CD8+ T Cell HomeostasisCho et al.ImmunityFebruary 4, 2010In BriefT cell receptor (TCR) contact with self ligands keeps T cells alive and is shown here to cause naive CD8+, but not CD4+, T cells to be hypersensitive to certain γc cytokines, notably interleukin (IL)-2, IL-15, and IL-7. Hypersensitivity of CD8+ T cells to IL-2 was dependent on a low-level TCR signal, associated with high expression of CD5 and GM1, a marker for lipid rafts, and was abolished by disruption of lipid rafts. By contrast, CD4+ T cells expressed low amounts of GM1 and were unresponsive to IL-2. Full-Text PDF Open Archive" @default.
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• W2057896643 title "T Cells Use Rafts for Survival" @default.
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