Role of 4-1BB in Allograft Rejection Mediated by CD8+ T Cells

The Journal of Immunology

et al. 2008

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.

Section: Discussionmentioning

confidence: 99%

The Role for Monocyte Chemoattractant Protein-1 in the Generation and Function of Memory CD8+ T Cells

Wang

The Journal of Immunology

et al. 2008

“…We studied CD8 ϩ , but not CD4 ϩ , memory T cells in this allogeneic setting because 1) immune regulation in vivo results in a long-lasting CD8 ϩ memory but a declining CD4 ϩ memory pool over time (44,45); 2) memory CD8 ϩ T cells are resistant to the conventional costimulatory blockade (22,23,46) and therefore could be resistant to tryptophan catabolism; and 3) memory CD8 ϩ T cells can be generated in response to an alloantigen independently of CD4 ϩ T cell help (32), suggesting that memory CD8 ϩ T cells are independent and may pose a more serious threat to tolerance induction than their CD4 ϩ counterparts. Our studies demonstrate that memory CD8 ϩ T cells are subject to the regulation mediated by tryptophan catabolism.…”

Section: Discussionmentioning

confidence: 99%

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Liu

The Journal of Immunology

et al. 2007

Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO. We found that overexpression of IDO in vivo attenuated the generation of both central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of TCM cells or TCM cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, TCM cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of TEM cells or TEM cell-mediated allograft rejection, suggesting that TEM cells, unlike TCM cells, do not require tryptophan for their effector function once they are generated. This study provides insight into the mechanisms underlying the differential regulation of memory T cell responsiveness and has clinical implications for vaccination or tolerance induction.

“…We studied CD8+, but not CD4+, memory T cells in this setting because: (1) allospecific CD8+ T cells from transgenic mice are available for tracking in vivo; (2) immune regulation results in a long-lasting CD8+ memory but a declining CD4+ memory pool (48,49) and (3) memory CD8+ T cells are resistant to conventional costimulatory blockade (1,2,50). Our studies identified CD8+ memory and IL-7 as a target to induce long-term allograft survival or tolerance.…”

Section: Discussionmentioning

confidence: 99%

Neutralizing IL-7 Promotes Long-Term Allograft Survival Induced by CD40/CD40L Costimulatory Blockade

Wang

American Journal of Transplantation

Liu

et al. 2006

Memory T cells are somewhat resistant to immunosuppresion. They therefore pose a threat to inducing long-term allograft survival. IL-7 is essential for memory T-cell generation. Here, we investigated whether neutralizing IL-7 promotes allograft survival. We found that neutralizing IL-7 alone did not significantly prolong allograft survival. However, blocking both IL-7 and CD154 signaling synergistically prolonged allograft survival. In contrast, neutralizing IL-2 failed to further prolong allograft survival induced by CD40/CD154 costimulatory blockade. Allospecific memory CD8+ T-cell generation was severely impaired under the treatment of anti-IL-7 plus anti-CD154 Ab while administering recombinant IL-7 enhanced CD8+ memory generation even under donor-specific transfusion plus anti-CD154 Ab treatment. Neutralizing IL-7, but not IL-2, together with blocking CD154 synergistically suppressed the proliferation of naïve/effector CD8+ T cells infiltrating grafts. Nevertheless, neutralizing IL-7 did not alter regulatory T-cell generation while neutralizing IL-2 suppressed their generation. Hence, targeting IL-7 represents a new strategy to prolong allograft survival by acting on both naïve and memory T cells. Long-term allograft survival may be achieved by neutralizing IL-7 plus CD40/CD154 blockade, since CD40/CD154 costimulatory blockade prevents acute rejection while neutralizing IL-7 suppresses the generation of memory T cells that persist and mediate late or chronic rejection.