MicroRNA-17~92 drives metabolic programming of virus-specific effector CD4 and CD8 T cell responses

Abstract

The miR-17[~]92 microRNA cluster drives oncogenesis by inducing proliferation and survival of cancer cells. A similar pro-proliferative role of miR-17[~]92 has also been identified in pathogen- and tumor-reactive T cells. However, the metabolic underpinnings of miR-17[~]92-drivenT cell expansion and effector differentiation remain undefined. Using a murine model of conditional miR-17[~]92 deletion or constitutive overexpression in viral antigen-specific CD4 or CD8 T cells, here we show that miR-17[~]92 drives terminal differentiation of CD4 and CD8 T cells through sustained activation of mTOR and glycolytic bioenergetics pathways. Constitutively increased expression of miR-17[~]92 led to a universal increase in the numbers of antigen-specific T follicular helper (TFH), T helper 1 (TH1) and cytotoxic T lymphocyte (CTL) effector subsets. During early stages of T cell activation, miR-17[~]92 overexpression was associated with increased glucose uptake and heightened glycolytic and oxidative metabolism to sustain increased proliferation in both CD4 and CD8 T cells. However, prolonged overexpression of miR-17[~]92 led to a loss of polyfunctionality and compromised metabolic fitness (glycolysis and mitochondrial respiration) by the peak of the effector responses. These studies establish miR-17[~]92 as a critical driver of T cell proliferation and effector differentiation through metabolic regulation of both effector CTL and CD4 T cell subsets (TFH and TH1) that are critical for combating viral infections. These studies form the basis for future manipulation of miR-17[~]92 gene/metabolic regulatory network to commandeer T cell immunity during infection, vaccination or cancer immunotherapy.