title: A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity.
abstract: 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.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Rao
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.forename: Kristen
authors.initials: K
authors.lastname: Pollizzi
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.forename: Protul A
authors.initials: PA
authors.lastname: Shrikant
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D006706:Homeostasis; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*
chemical_list: C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases