mTOR REGULATES CD4 AND CD8 EFFECTOR T CELL DIFFERENTIATION VIA SERUM- AND GLUCOCORTICOID-REGULATED KINASE 1 (SGK1)
Embargo until
2019-05-01
Date
2015-03-11
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Publisher
Johns Hopkins University
Abstract
The AGC kinases comprise approximately 10% of mammalian kinases, and are broadly involved in regulating metabolism, survival and differentiation. While much is known about S6 Kinase and Akt, the precise downstream targets and functions of other enzymes in this family have yet to be determined. Serum- and glucocorticoid-regulated kinase 1 (SGK1) is an AGC kinase that plays a role in regulating membrane sodium channel expression in renal tubular cells in response to increases in serum osmolarity in an mTORC2-dependent manner. We hypothesized that SGK1 might represent a novel mTORC2-depednent downstream regulator of T cell differentiation and function. Here we show that SGK1 is a critical regulator of CD4+ effector differentiation into Th1 and Th2 subsets. Specifically, upon activation by mTORC2, SGK1 promotes Th2 differentiation by negatively regulating the NEDD4-2 E3 ligase mediated destruction of JunB. Simultaneously, SGK1 represses the production of IFN-γ by controlling the expression of the long isoform of TCF-1. Consistent with these functions, mice in which SGK1 has been selectively deleted in T cells fail to generate a robust Th2 response and are resistant to experimentally induced asthma. Likewise, such mice generate robust levels of IFN-γ in response to vaccines and more readily reject tumors. Loss of SGK1 in CD8+ T cells leads to inappropriate expression of memory markers such as CD127 and eomesodermin on effector cells, and subsequently may lead to enhanced memory differentiation. Overall these results reveal a novel role for SGK1 in promoting a signaling program that simultaneously enhances IL-4 production and inhibits IFN-γ expression. Given the ubiquitous expression of SGK1 in mammalian cells, these findings provide novel insight into the ability of AGC kinases to regulate cellular function in response to the environment.
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Keywords
mTOR, T cell differentiation, T cell metabolism