A Novel mTORC1-Dependent, Akt-Independent Pathway Differentiates the Gut Tropism of Regulatory and Conventional CD4 T Cells

Abstract

The vitamin A metabolite all-trans retinoic acid (ATRA) induces a gut-homing phenotype in activated CD4+ conventional T cells (Tconv) by upregulating the integrin α4β7 and the chemokine receptor CCR9. We report that, in contrast to mouse Tconv, only about 50% of regulatory T cells (Treg) upregulate CCR9 when stimulated by physiological levels of ATRA, even though Tconv and Treg express similar levels of the retinoic acid receptor (RAR). The resulting bimodal CCR9 expression is not associated with differences in the extent of their proliferation, level of Foxp3 expression, or affiliation with naturally-occurring Treg (nTreg) or induced Treg (iTreg) in the circulating Treg pool. Furthermore, we find that exposure of Treg to the mechanistic target of rapamycin (mTOR) inhibitor rapamycin suppresses upregulation of both CCR9 and α4β7, an effect that is not evident with Tconv. This suggests that in Treg, ATRA-induced upregulation of CCR9 and α4β7 is dependent on activation of an mTOR signaling pathway. The involvement of mTOR is independent of Akt activity, since specific inhibition of Akt, pyruvate dehydrogenase kinase-1, or its downstream target glycogen synthase kinase-3, did not prevent CCR9 expression. Additionally, Rictor (mTOR complex [C] 2)-deficient Treg showed unaltered ability to express CCR9, whereas Raptor (mTORC1)-deficient Treg were unable to upregulate CCR9, suggesting the selective participation of mTORC1. These findings reveal a novel difference between ATRA signaling and chemokine receptor induction in Treg versus Tconv and provide a framework via which the migratory behavior of Treg versus Tconv might be regulated differentially for therapeutic purposes.

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

“…Chen LC et al . [ 110 ] have recently studied CCR9 expression in expanded murine Treg cells showing that only 50% of Treg up-regulate CCR9 when stimulated by atRA. Additionally, they showed that CCR9 and α4β7 do not follow the same signal pathways, whereas the expression of CCR9 is mTORC1-dependent.…”

Metabolic Pathways Involved in Regulatory T Cell Functionality

“…(B) To support the increased need for energy during migration, Treg increase their glycolytic flux. Metabolic shifts in other pathways have not been described for Treg migration (15, 16, 33–39). (C) Treg show decreased glycolysis and increased OXPHOS, FAO, FAS and tryptophan metabolism during their phase of suppressive function.…”

“…Exposure of Treg to the mTOR inhibitor rapamycin suppresses upregulation of both α4β7 and CCR9, suggesting that the mechanism is mTOR-dependent. Strikingly, rapamycin-insensitive companion of mTOR (RICTOR) or (mTORC2)-deficient Treg have unaltered ability to express CCR9, while RAPTOR(mTORC1)-deficient Treg are unable to upregulate CCR9, suggesting the selective participation of mTORC1 in the regulation of Treg motility (39). Loss of phosphatase and tensin homolog (PTEN) also impacts migration by lowering CD62L and CCR7 expression (54).…”

mTOR signaling in the differentiation and function of regulatory and effector T cells

“…The vitamin A metabolite all-trans retinoic acid (RA) endows guthoming phenotypes in T cells by upregulating the integrin α4β7 and chemokine receptor CCR9. Treatment with rapamycin or RAPTOR deficiency, but not RICTOR deficiency, prevents RA-induced CCR9 expression in Tregs, suggesting that RA promotes gut tropism through mTORC1 [45]. …”