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Henao-Mejia, Jorge; Williams, Adam; Goff, Loyal A; Staron, Matthew; Licona-Limon, Paula; Kaech, Susan M; Nakayama, Maki; Rinn, John L; Flavell, Richard A (2013)

THE MICRORNA MIR-181 IS A CRITICAL CELLULAR METABOLIC RHEOSTAT ESSENTIAL FOR NKT CELL ONTOGENESIS AND LYMPHOCYTE DEVELOPMENT AND HOMEOSTASIS

Immunity 38(5):984-997
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Regulation of metabolic pathways in the immune system provides a mechanism to actively control cellular function, growth, proliferation, and survival. Here, we report that miR-181 is a nonredundant determinant of cellular metabolism and is essential for supporting the biosynthetic demands of early NKT cell development. As a result, miR-181-deficient mice showed a complete absence of mature NKT cells in the thymus and periphery. Mechanistically, miR-181 modulated expression of the phosphatase PTEN to control PI3K signaling, which was a primary stimulus for anabolic metabolism in immune cells. Thus miR-181-deficient mice also showed severe defects in lymphoid development and T cell homeostasis associated with impaired PI3K signaling. These results uncover miR-181 as essential for NKT cell development and establish this family of miRNAs as central regulators of PI3K signaling and global metabolic fitness during development and homeostasis.