A Central Role for mTOR Kinase in Homeostatic Proliferation Induced CD8⁺ T Cell Memory and Tumor Immunity

The cell-intrinsic mechanisms guiding naive CD8⁺ T cells for clonal expansion and memory generation via homeostatic proliferation (HP) are unclear. Here, we have shown that HP of naive CD8⁺ T cells requires IL-7-, but not IL-15-induced mTOR kinase activation. HP-induced mTOR enhances transcription factor T-bet for functional maturation and CD122 expression, which sensitizes for an IL-15-dependent memory transition by favoring transcription factor Eomesodermin over T-bet. Inhibition of mTOR blocks T-bet and CD122 expression but preserves memory in an IL-15-independent manner by promoting Eomesodermin expression. The ability of rapamycin to augment HP-induced memory was cell-intrinsic given that silencing mTOR in CD8⁺ T cells generated identical outcomes. Strikingly, HP-induced CD8⁺ T cell memory generated by IL-15-dependent or -independent mechanisms demonstrated identical tumor efficacy. These results indicate a central role for mTOR in HP-induced CD8⁺ T cell responses and demonstrate the importance for CD8⁺ memory in HP-induced tumor efficacy.