Recent convincing data have shown that naturally occurring CD8+CD122+ T cells are also regulatory T cells. Paradoxically, CD8+CD122+ T cells have been well described as memory T cells. Given their critical role in tolerance versus long-term immunity, it is important to reconcile this profound dichotomy. In this study, we reported that CD8+CD122+ T cells contain both programmed death-1 (PD-1)− and PD-1+ populations. It was CD8+CD122+PD-1+ T cells, but not their PD-1− counterparts, that suppressed T cell responses in vitro and in vivo. This suppression was largely dependent on their production of IL-10. Moreover, the costimulatory signaling of both CD28 and PD-1 is required for their optimal IL-10 production. In contrast, Ag-specific CD8+CD122+PD-1− T cells were bona fide memory T cells. Thus, CD8+CD122+ T cells can be either regulatory T or memory T cells, depending on their PD-1 expression and Ag specificity. This study reconciles previously contradictory findings and has important implications for tolerance induction.
The constitutive expression of PD-L1 in the testis is an important mechanism underlying testicular immune privilege and long-term survival of intratesticular islet allografts.
Memory T cells respond faster and more vigorously than their naive counterparts and are critical for adaptive immunity. However, it is unknown whether and how memory T cells react in the face of irrelevant Ags. It is generally accepted that bystander memory T cells are neutral in immune responsiveness. In this study, we present the first evidence that bystander central memory (TCM), but not effector memory (TEM), CD8+ T cells suppress allograft rejection as well as T cell proliferation in the draining lymph nodes (DLN) of recipient mice. Both bystander TCM and naive T cells, but fewer TEM cells, migrated to DLN, whereas TCM cells exhibited faster turnover than their naive counterparts, suggesting that bystander TCM cells have an advantage over their naive counterparts in suppression. However, bystander TEM cells migrated to inflammatory graft sites, but not DLN, and yet failed to exert their suppression. These findings indicate that bystander memory T cells need to migrate to lymph nodes to exert their suppression by inhibiting responder T cell activation or homeostatic proliferation. Moreover, the suppression mediated by bystander TCM cells was largely dependent on IL-15, as IL-15 was required for their homeostatic proliferation and TCM-mediated suppression of allograft rejection. This suppression also required the presence of TGFβ1, as TCM cells expressed TGFβ1 while neutralizing TGFβ1 abolished their suppression. Thus, bystander TCM, but not TEM, CD8+ T cells are potent suppressors rather than bystanders. This new finding will have an impact on cellular immunology and may have clinic implications for tolerance induction.
Memory T cells are resistant to the conventional costimulatory blockade and therefore impede tolerance induction. However, their migratory, survival, and functional requirements for chemokines are not well understood. We herein examine the role for MCP-1 or CCL2 in the generation, migration, and function of memory CD8+ T cells. We found that overall generation of both central memory (TCM) and effector memory (TEM) CD8+ T cells was severely impaired in the absence of MCP-1. Importantly, the survival of TEM, but not TCM, CD8+ cells was reduced without MCP-1, whereas the homeostatic proliferation of TCM, but not TEM, CD8+ cells was weakened in MCP-1−/− mice. However, once they were generated in the absence of MCP-1, in vitro function of both subsets of memory cells remained intact as determined by their proliferation and IFN-γ production. Interestingly, the migration of TCM, but not TEM, CD8+ cells to inflammatory sites was significantly delayed without MCP-1, whereas both subsets of memory cells underwent comparable expansion and apoptosis with or without MCP-1 during the effector phase. Moreover, the function to eliminate a graft of TCM, but not TEM, CD8+ cells was impaired without MCP-1. Thus, this study demonstrates that MCP-1 plays an important role in not only migration but also generation and survival of memory T cells. This finding provides new insight into the requirement of chemokines for the generation, survival, and function of differential subsets of memory T cells and may have clinic implications for tolerance induction.
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