The coexpression of Tim-3 and PD-1 leads to CD8 T cell exhaustion in aged female mice (LYM4P.760)

T cells, which are major components of adaptive immune system, are dysfunctional in aged individuals due to numerous intrinsic and extrinsic changes of aged T cell. Recently, several studies have shown that the expression of inhibitory receptors is increased on CD8 T cells from aged mice, which is also observed on exhausted CD8 T cells in chronic infection model, by which effector T cells are negatively regulated. In this study, we described that Tim-3+ PD-1+ CD8 T cells increased in aged mice compared to those of young mice. The more extensive investigations on the functional characteristics of aged Tim-3+ PD-1+ CD8 T cell revealed that these cells had defects in cytokine (IFN-γ, TNF-α) production and proliferation, consistent with features of exhausted CD8 T cell in a chronic infection model. Aged Tim-3+ PD-1+ CD8 T cell produced more immune regulatory cytokine, IL-10, than PD-1 single positive or Tim-3 and PD-1 double negative CD8 T cells. Furthermore, there was more diminished homeostatic proliferation of aged Tim-3+ PD-1+ CD8 T cells than other subsets in lymphopenic conditions, indicating that aged Tim-3+ PD-1+ CD8 T cell had cell-intrinsic defect in proliferation capacity. Interestingly, adoptively transferred aged Tim-3+ PD-1+ CD8 T cells in naive B6 hosts survived longer than other subsets. Collectively, our findings on aged Tim-3+ PD-1+ CD8 T cell would provide a important insight for understanding the defect in the immune senescence.