Metabolic control of regulatory T cell development and function

Abstract

Foxp3(+) regulatory T cells (Tregs) maintain immune tolerance and play an important role in immunological diseases and cancers. Recent studies have revealed an intricate relationship between Treg biology and host and microbial metabolism. Various metabolites or nutrients produced by host and commensal microbes, such as vitamins and short-chain fatty acids (SCFAs), regulate Treg generation, trafficking, and function. Furthermore, cell intrinsic metabolic programs, orchestrated by mTOR and other metabolic sensors, modulate Foxp3 induction and Treg suppressive activity. Conversely, Tregs are crucial in regulating obesity-associated inflammation and host metabolic balance, and in shaping homeostasis of gut microbiota. We review here the interplay between Tregs and metabolism, with a particular focus on how host, commensal, and cellular metabolism impinge upon Treg homeostasis and function.

Keywords: SCFA; commensal microbiota; mTOR; metabolism; obesity; vitamin.

Figure 1. Host metabolism modulates Treg homeostasis

RA, a vitamin A metabolite produced by GALT CD103⁺ DC, induces the conversion of naïve CD4⁺ T cells to Tregs. Vitamin B₃ binds to GPR109a on GALT DCs and other innate immune cells, allowing these cells to induce Foxp3 expression in naïve T cells. Vitamin D₃, through its metabolite 1,25 (OH)₂VD₃ and the receptor VDR, enhances Foxp3 gene transcription by binding to the Foxp3 promoter locus. The vitamin B₉ metabolite tetrahydrofolate maintains Treg survival. Leptin, produced by adipocyte and Tregs, restrains Treg proliferation and abundance.

Figure 2. Commensal microbial metabolism controls Treg homeostasis in the colon

Colonization of mice with Clostridia species from both mouse and human feces leads to increased Treg abundance in the colon. SCFAs, metabolites through bacteria fermentation of dietary fiber, promote Treg expansion and de novo generation. Clostridia species also stimulate conventional T cells to produce IL-2, which promotes colonic Treg proliferation. B. fragilis produces PSA that can induce Treg induction and potentiate Tregs to produce regulatory cytokines such as IL-10. In a feedback loop, Tregs contribute to diversification of Clostridia species by promoting generation and selection of IgA.

Figure 3. mTOR signaling in Tregs and conventional T cells

(A) In Tregs, TCR and IL-2 signaling promotes Treg proliferation and function by activating mTORC1-dependent lipid biosynthesis, particularly the mevalonate pathway. mTORC1 also promotes Treg function through inhibition of mTORC2 activity. VAT-associated Tregs exhibit increased expression of PPAR-γ, which promotes fatty acid metabolism and hence stimulates the accumulation and suppressive phenotypes of Tregs residing in adipose tissue. (B) In conventional T cells, mTOR signaling inhibits Foxp3 induction partly by inducing HIF1α expression and HIF1α-dependent glycolysis. mTOR signaling promotes T_H1, T_H2, T_H17 and effector CD8⁺ T cell differentiation. However, mTORC1 signaling negatively regulates memory CD8⁺ T cell differentiation. Whether and how mTOR signaling controls Tfh differentiation is currently unknown.

Figure 3. mTOR signaling in Tregs and conventional T cells

(A) In Tregs, TCR and IL-2 signaling promotes Treg proliferation and function by activating mTORC1-dependent lipid biosynthesis, particularly the mevalonate pathway. mTORC1 also promotes Treg function through inhibition of mTORC2 activity. VAT-associated Tregs exhibit increased expression of PPAR-γ, which promotes fatty acid metabolism and hence stimulates the accumulation and suppressive phenotypes of Tregs residing in adipose tissue. (B) In conventional T cells, mTOR signaling inhibits Foxp3 induction partly by inducing HIF1α expression and HIF1α-dependent glycolysis. mTOR signaling promotes T_H1, T_H2, T_H17 and effector CD8⁺ T cell differentiation. However, mTORC1 signaling negatively regulates memory CD8⁺ T cell differentiation. Whether and how mTOR signaling controls Tfh differentiation is currently unknown.