Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb

Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell...

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Vydáno v:	Immunity (Cambridge, Mass.) Ročník 51; číslo 6; s. 1012
Hlavní autoři:	Shi, Hao, Chapman, Nicole M, Wen, Jing, Guy, Cliff, Long, Lingyun, Dhungana, Yogesh, Rankin, Sherri, Pelletier, Stephane, Vogel, Peter, Wang, Hong, Peng, Junmin, Guan, Kun-Liang, Chi, Hongbo
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 17.12.2019
Témata:	Animals Arginine - metabolism Cell Cycle Cell Differentiation - physiology Cell Line Humans Immune Tolerance - immunology Leucine - metabolism Lymphocyte Activation - immunology Mechanistic Target of Rapamycin Complex 1 - metabolism Mice Mice, Inbred C57BL Mice, Knockout Monomeric GTP-Binding Proteins - genetics Monomeric GTP-Binding Proteins - metabolism Ras Homolog Enriched in Brain Protein - genetics Ras Homolog Enriched in Brain Protein - metabolism Receptors, Antigen, T-Cell - immunology T-Lymphocytes, Regulatory - cytology T-Lymphocytes, Regulatory - immunology autoimmunity Rheb eTreg cells amino acids mTOR Treg cells metabolism RagB RagA
ISSN:	1097-4180, 1097-4180
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Popis
Shrnutí:	Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4180 1097-4180
DOI:	10.1016/j.immuni.2019.10.001