Editors' ChoiceImmunometabolism

Battling over mTORC1 in Treg cells

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Sci. Signal.  29 Nov 2016:
Vol. 9, Issue 456, pp. ec281
DOI: 10.1126/scisignal.aal4603

Upon activation, naïve CD4+ T cells can differentiate into effector T cells, which promote immune responses, or into regulatory T (Treg) cells, which suppress effector T cells to prevent inflammation and autoimmunity. Activation of T cells also changes their metabolic state. Effector T cells switch from oxidative to glycolytic metabolism, which is supported by the increased cell surface abundance of the glucose transporter Glut1, and which enables cell proliferation and effector function. Gerriets et al. found that mouse Treg cells could be divided into proliferative and nonproliferative cells based on their relative abundance of the proliferation marker Ki67. Ki67hi Treg cells had increased Glut1 abundance and enhanced mTORC1 activation (hallmarks of effector T cells) compared with Ki67lo Treg cells. Stimulation of proliferating Treg cells with the Toll-like receptor 1 (TLR1) and TLR2 agonist Pam3CSK4 further increased Glut1 abundance and proliferation; however, these cells had impaired suppressor function. Overexpression of the transcriptional regulator Foxp3, which is required for Treg cell generation and maintenance, resulted in the decreased abundance of Glut1 and inhibition of the phosphoinositide 3-kinase (PI3K)–Akt–mTORC1 signaling pathway, which led to reduced glycolysis. Treg cells from transgenic mice expressing constitutively active Akt were larger than their wild-type counterparts and had increased abundance of activation markers, but their suppressive function was less efficient. Similarly, Treg cells from Glut1 transgenic (Glut1-tg) mice exhibited enhanced growth and proliferation and increased glycolysis but had decreased suppressor function. Adoptive transfer of wild-type Treg cells reversed disease progression in a mouse model of inflammatory bowel disease. In contrast, adoptively transferred Glut1-tg Treg cells were much less effective. Furthermore, the Glut1-tg Treg cells had decreased Foxp3 abundance compared with that of wild-type cells and were decreased in number. Together, these data suggest that inflammatory stimuli (through TLRs) and Foxp3 have opposing effects on Treg cell growth, proliferation, and function by differentially regulating mTORC1 function and glucose metabolism.

V. A. Gerriets, R. J. Kishton, M. O. Johnson, S. Cohen, P. J. Siska, A. G. Nichols, M. O. Warmoes, A. A. de Cubas, N. J. MacIver, J. W. Locasale, L. A. Turka, A. D. Wells, J. C. Rathmell, Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016). [PubMed]