The mammalian Target of Rapamycin (mTOR) regulates T helper cell differentiation through the selective activation of mTORC1 and mTORC2 signaling

By Greg M. Delgoffe, Kristen N. Pollizzi, A. Waickman, Emily B. Heikamp, D. Meyers, M. Horton, B. Xiao, P. Worley, J. Powell. Nature Immunology, 2011

935 citations recorded by the source corpus.

The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the TH1 and TH17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate TH1 and TH17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become TH2 cells. Alternatively, when mTORC2 signaling was deleted from T cells, they failed to generate TH2 cells in vitro and in vivo but preserved their ability to become TH1 and TH17 cells. Our data identify mechanisms by which two distinct signaling pathways downstream of mTOR regulate helper cell fate in different ways. These findings define a previously unknown paradigm that links T cell differentiation with selective metabolic signaling pathways.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b60b82ad40b77d4e226499cbf4eaa616ef5a1bd2

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Citations in the corpus

Deletion of the gene Pip4k2c, a novel phosphatidylinositol kinase, results in hyperactivation of the immune system (2016, background): “Our studies suggest that mTORC1, which regulates the immune system in diverse aspects, including modulating T-cell differentiation and activation (12), is required to maintain the inflammatory phenotype in Pip4k2c mice.”
Unraveling the Complex Interplay Between T Cell Metabolism and Function (2018, background): “For example, mTOR signals promote Th1 and Th17 cell differentiation (96), while mTOR inhibition blocks effector-like T helper (Th) cells and skews differentiation toward forkhead box P3 (FoxP3)-expressing regulatory T cells (Tregs) (97– 101).”
Regulation of Immune Responses by mTOR (2011, background): “Indeed, our group (looking at T cells) and other groups (examining different tissues) have shown that upstream Akt activation as measured by threonine 308 phosphorylation is robust even in the absence of mTORC2 activity (14, 42).”
The Balance of Th17 versus Treg Cells in Autoimmunity (2018, background): “Mice deficient in mTORC1 activity cannot generate Th17 responses [76].”
T cell metabolism drives immunity (2015, background): “Both Akt and mTOR promote aerobic glycolysis and support effector T cell differentiation, growth, and function (Delgoffe et al., 2011; Pollizzi et al., 2015).”
Glucose Metabolism Regulates T Cell Activation, Differentiation, and Functions (2014, background): “As follows, signaling from the mTORC1 is required for the differentiation of Th1 and Th17 but not of Th2 cells (46).”