Exhaustion of T cells limits their ability to clear chronic infections or eradicate tumors. Here, in the context of transplantation, we investigated whether T-cell exhaustion occurs and has a role in determining transplant outcome. A peptide/MHC tetramer-based approach was used to track exhausted CD8 T cells in a male-to-female skin transplantation model. Transplantation of large-size whole-tail skins, but not small-size tail skins (0.8 cm x 0.8 cm), led to exhaustion of anti-male tetramer CD8 T cells and subsequently the acceptance of skin grafts. To study CD4 T-cell exhaustion, we used the TCR-transgenic B6 TEa cells that recognize a major transplant antigen I-Eα from Balb/c mice. TEa cells were adoptively transferred either into B6 recipients that received Balb/c donor skins, or into CB6F1 mice that contained an excessive amount of I-Eα antigen. Adoptively transferred TEa cells in skin-graft recipients were not exhausted. By contrast, virtually all adoptively transferred TEa cells were exhausted in CB6F1 mice. Those exhausted TEa cells lost ability to reject Balb/c skins upon further transfer into lymphopenic B6.Rag1 mice. Hence, T-cell exhaustion develops in the presence of abundant antigen and promotes transplant acceptance. These findings are essential for better understanding the nature of transplant tolerance.
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