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

Abstract

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 aciddependent 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.

mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions

“…206 T-follicular regulatory (Tfr) cells, require mTOR signaling for their generation or homeostasis. 23,61,115,207,208,209 Similar observation is found in Treg cells deficient in c-MYC, the transcription factor that frequenlty interplays with mTORC1 in programming anabolic metabolism. 210 Furthermore, mTOR signaling supports the accumulation of pTreg cells in vivo, 115 demonstrating that mTOR signaling has discrete functions during pTreg-cell formation and maintenance.…”

“…59,60 Recently, we have also shown that amino acids can regulate mTORC1 activity in Treg cells by driving dissociation of the TSC complex from the lysosome, which likely allows RHEB to activate mTORC1 in cooperation with the Rag complex. 23 The indispensable role of the Rag complex in Treg cell-suppressive function through sensing amino acid availability has been uncovered by another independent study. 61 Thus, amino acids are critical activators for mTORC1 activity in T cells.…”

“…Individual amino acids, such as arginine, leucine, glutamine, L-cysteine, and methionine, have been shown to support mTORC1 activation in different T-cell subsets. 23,52,53,54,55,56 Moreover, the amino acid transporters CD98-LAT1 and ASCT2 are important for driving mTORC1 activation in naive T cells, activated T cells, and Treg cells. [54][55][56][57][58] The asymmetric segregation of amino acid transporters leads to altered mTOR accumulation in the DC-proximal and DC-distal daughter cells during the first division of CD8 + T cells, which ultimately contributes to fate decisions of memory-like and effector-like CD8 + T cells.…”

Immunometabolism: From basic mechanisms to translation

“…In the absence of mTORC1 function, Tregs fail to suppress effector T cells and severe autoimmunity can ensue. 39,40 However, AMPK can promote Treg accumulation in vivo 10 and may do so in part by moderating mTORC1 activity, as the mTORC1 inhibitor rapamycin can promote development of Treg. 41 These findings about regulator and effector T cells demonstrate that factors that balance and fine-tune mTORC1 signaling function to integrate microenvironmental nutrients and signals and are fundamental elements of immunometabolic signaling.…”

Metabolic Control of Treg Cell Stability, Plasticity, and Tissue-Specific Heterogeneity

“…Intracellular metabolites and metabolic pathways also modulate the expression of Foxp3, as well as Treg cell transcriptional programs and functional plasticity (20,21,23). In particular, nutrient-fueled mTORC1 activation promotes metabolic reprogramming in Treg cells in vivo, with increased lipogenesis and mevalonate pathway-dependent cholesterol biosynthesis to support Treg cell proliferation and function (22,24). However, inappropriate mTORC1 activation and unconstrained glycolysis in Treg cells lead to decreased Foxp3 expression and reduced Treg cell suppressive activity, indicating that cellular metabolism plays essential roles for regulating Foxp3 stability and Treg cell function (18,(25)(26)(27).…”