The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex

Heikamp, Emily; Patel, Chirag H.; Collins, Sam; Waickman, Adam T.; Oh, Min Hee; Sun, Im-Hong; Illei, Peter B.; Sharma, Archna; Náray-Fejes-Tóth, Anikó; Fejes-Tóth, Géza; Misra-Sen, Jyoti; Horton, Maureen R.; Powell, Jonathan D.

doi:10.1038/ni.2867

Cited by 168 publications

(170 citation statements)

References 42 publications

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“…In contrast, the mTORC1 pathway regulates metabolic programs to facilitate the switch from quiescent to activated T cell and plays a critical role in Th17 cell differentiation (53,54). Meanwhile, mTORC2 through its substrate SGK1 regulates the ability of Th cells to differentiate into Th2 cells (55,56). Interestingly, availability of significant levels of amino acids is critical to mTORC1 function, and amino acid depletion rapidly inactivates mTORC1 signaling, inhibiting Th17 cell differentiation (57).…”

Section: Discussionmentioning

confidence: 99%

Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis

Negrotto

Correale

2017

The Journal of Immunology

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Amino acid catabolism has been implicated in immunoregulatory mechanisms present in several diseases, including autoimmune disorders. Our aims were to assess expression and activity of enzymes involved in Trp and Arg catabolism, as well as to investigate amino acid catabolism effects on the immune system of multiple sclerosis (MS) patients. To this end, 40 MS patients, 30 healthy control subjects, and 30 patients with other inflammatory neurological diseases were studied. Expression and activity of enzymes involved in Trp and Arg catabolism (IDO1, IDO2, Trp 2,3-dioxygenase [TDO], arginase [ARG] 1, ARG2, inducible NO synthetase) were evaluated in PBMCs. Expression of general control nonrepressed 2 serine/threonine kinase and mammalian target of rapamycin (both molecules involved in sensing amino acid levels) was assessed in response to different stimuli modulating amino acid catabolism, as were cytokine secretion levels and regulatory T cell numbers. The results demonstrate that expression and activity of IDO1 and ARG1 were significantly reduced in MS patients compared with healthy control subjects and other inflammatory neurological diseases. PBMCs from MS patients stimulated with a TLR-9 agonist showed reduced expression of general control nonrepressed 2 serine/threonine kinase and increased expression of mammalian target of rapamycin, suggesting reduced amino acid catabolism in MS patients. Functionally, this reduction resulted in a decrease in regulatory T cells, with an increase in myelin basic protein–specific T cell proliferation and secretion of proinflammatory cytokines. In contrast, induction of IDO1 using CTLA-4 or a TLR-3 ligand dampened proinflammatory responses. Overall, these results highlight the importance of amino acid catabolism in the modulation of the immunological responses in MS patients. Molecules involved in these pathways warrant further exploration as potential new therapeutic targets in MS.

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Section: Discussionmentioning

confidence: 99%

Amino Acid Catabolism in Multiple Sclerosis Affects Immune Homeostasis

Negrotto

Correale

2017

The Journal of Immunology

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“…By contrast, CD4 + T cells that lack RICTOR, and thus lack mTORC2 signaling, are readily skewed toward Th1 or Th17 cell lineages, but fail to differentiate into Th2 cells (5,7). In addition, RICTORdeficient mice are resistant to Th2 cell-mediated diseases (5,8). These observations provide convincing evidence that mTORC1 is required for Th1 and Th17 cell differentiation, and that mTORC2 is necessary for Th2 cell development.…”

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confidence: 82%

mTOR Complex Signaling through the SEMA4A–Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells

Ito

Nojima

Nishide

et al. 2015

The Journal of Immunology

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Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4+ T cell responses, the involvement of mTOR in CD8+ T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8+ T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A−/− CD8+ T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8+ T cell responses were significantly impaired in SEMA4A−/− mice. Furthermore, SEMA4A−/− CD8+ T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8+ T cells. IFN-γ production and mTORC1 activity in SEMA4A−/− CD8+ T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8+ T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8+ T cells, but also reveal a novel link between a semaphorin and mTOR signaling.

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“…While levels of SGK1 expression contribute to hypertension and renal disease, transcriptional network analysis identified Sgk1 as a key node for the induction of Th17 cells (25,34). Moreover, recently SGK1 was shown to have an effect on other Th cellular subsets (35). SGK1-mediated induction of proinflammatory Th17 cells occurs in tandem with activation of p38/MAPK and NFAT5 pathways, leading to a FOXO1-dependent increase in expression of the IL-23 receptor and heightened signaling for the IL-17 inflammatory cascade (24,25).…”

Section: + Regulatory T Cellsmentioning

confidence: 99%