T Cells Encountering Myeloid Cells Programmed for Amino Acid-dependent Immunosuppression Use Rictor/mTORC2 Protein for Proliferative Checkpoint Decisions

Abstract

Modulation of T cell proliferation and function by immunoregulatory myeloid cells are an essential means of preventing self-reactivity and restoring tissue homeostasis. Consumption of amino acids such as arginine and tryptophan by immunoregulatory macrophages is one pathway that suppresses local T cell proliferation. Using a reduced complexity in vitro macrophage-T cell co-culture system, we show that macrophage arginase-1 is the only factor required by M2 macrophages to block T cells in G, and this effect is mediated by l-arginine elimination rather than metabolite generation. Tracking how T cells adjust their metabolism when deprived of arginine revealed the significance of macrophage-mediated arginine deprivation to T cells. We found mTORC1 activity was unaffected in the initial G block. After 2 days of arginine deprivation, mTORC1 activity declined paralleling a selective down-regulation of SREBP target gene expression, whereas mRNAs involved in glycolysis, gluconeogenesis, and T cell activation were unaffected. Cell cycle arrest was reversible at any point by exogenous arginine, suggesting starved T cells remain poised awaiting nutrients. Arginine deprivation-induced cell cycle arrest was mediated in part by Rictor/mTORC2, providing evidence that this nutrient recognition pathway is a central component of how T cells measure environmental arginine.

l-Citrulline Metabolism in Mice Augments CD4+ T Cell Proliferation and Cytokine Production In Vitro, and Accumulation in the Mycobacteria-Infected Lung

“…As a preliminary step to determine if l -citrulline could be utilized to promote T cell functions, we assessed CD4 + T cell proliferation in l -arginine-free RPMI 1640 (R-free RPMI) supplemented with l -arginine, l -citrulline, or neither amino acid. Paralleling previous work ( 11 , 14 , 25 , 27 ), T cell proliferation was absent in l -arginine-deficient media compared with that supplemented with l -arginine (Figures 1 A–C). When l -citrulline was provided, T cells restored their proliferative ability to the same degree as l -arginine-cultured cells (Figures 1 A–C), indicating l -citrulline can rescue T cell proliferation when l -arginine is unavailable.…”

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

“…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.…”

Resolution of Cutaneous Leishmaniasis and Persistence ofLeishmania majorin the Absence of Arginase 1

“…This effect can contribute to the immune escape of microbial pathogens (28,29) or tumor cells (30,31); however, prevention of Th1 or Th2 cellmediated immunopathology by Arg1 has also been observed (32,33). Reported molecular mechanisms underlying the Arg1mediated T cell suppression are the downregulation of CD3z (34) and the induction of cell cycle arrest that was characterized by a failure to upregulate cyclin D2 and D3 (35,36), a decline of mTORC1 activity, and a repression of lipid biosynthesis-linked genes (36). Third, Arg1 was also found to deprive endothelial or type 3 NO synthase (NOS3) of L-arginine, which resulted in enhanced immune cell adhesion to vascular endothelium due to the lack of antiadhesive endothelial NO (37,38).…”