The energy sensitive kinase mTOR regulates T-bet mediated heritable type 1 effector cell fate of CD8 T cells (83.1)

Abstract

Abstract The inflammatory cytokine; IL-12, provides an essential third signal for CD8 effector cell fate determination. The molecular mechanisms by which IL-12 regulates STAT4 and T-bet activity for instructing effector cell fate remains unclear. The energy sensitive kinase; mTOR (mammalian target of rapamycin), a target of both the PI3K-Akt and/or AMPK signaling pathways has recently been shown to affect trafficking of effector CD8 T cells in vivo, however its role in cytokine determined effector cell fate remains untested. Using latex microspheres; H-2Kb/SIINFEKL and mB7.1, as surrogate antigen presenting constructs, we have established that the presence of IL-12 enhances and sustains antigen/B7.1 induced mTOR activity in naïve OT-1 T cells. The augmented mTOR activity requires PI3K as well as STAT4 and inhibition of mTOR; rapamycin or temsirolimus, leads to the loss of IL-12 induced sustained T-bet expression and subsequent loss of type I (IFNg) CD8 effector cell fate. Interestingly, inhibition of mTOR in IL-12 conditioned OT-1 cells produced only marginal decreases in cytolytic activity and increases in CD69, L-selectin and Eomesodermin expression. Hence, we have demonstrated a novel role for mTOR in integrating instructions to regulate effector cell fate in naïve CD8 T cells and characterized its mechanisms of action. Supported by NIH and RPCI Alliance Foundation