Metabolic control of the Treg/Th17 axis

Abstract

The interplay of the immune system with other aspects of physiology is continually being revealed and in some cases studied in considerable mechanistic detail. A prime example is the influence of metabolic cues on immune responses. It is well appreciated that upon activation, T cells take on a metabolic profile profoundly distinct from that of their quiescent and anergic counterparts; however, a number of recent breakthroughs have greatly expanded our knowledge of how aspects of cellular metabolism can shape a T-cell response. Particularly important are findings that certain environmental cues can tilt the delicate balance between inflammation and immune tolerance by skewing T-cell fate decisions toward either the T-helper 17 (Th17) or T-regulatory (Treg) cell lineage. Recognizing the unappreciated immune-modifying potential of metabolic factors and particularly those involved in the generation of these functionally opposing T-cell subsets will likely add new and potent therapies to our repertoire for treating immune mediated pathologies. In this review, we summarize and discuss recent findings linking certain metabolic pathways, enzymes, and by-products to shifts in the balance between Th17 and Treg cell populations. These advances highlight numerous opportunities for immune modulation.

Fig. 1. Reported and potential mechanisms for the regulation of the Th17/Treg balance by HIF-1

HIF-1 is upregulated in naïve Cd4⁺ T cells by a range of stimuli including TCR stimulation, LPS, mTORC1 activation, hypoxia, and pro-inflammatory cytokines. HIF-1 induces glycolysis genes that support the differentiation of Th17 cells. HIF-1 has also been reported to activate expression of the Th17 master regulator RORγt. HIF-1 then interacts with RORγt and p300 in order to induce optimal transcription at the il17 gene and other Th17 associated loci. HIF-1 also binds Foxp3 and mediates its proteosomal degradation. HIF-1 also drives expression of survival genes that aid in Th17 persistence. HIF-1 may also suppress expression of the anti-Th17 factor PPAR γ.

Fig. 2. The effect of metabolic factors on Th17 and iTreg differentiation

The process of glycolysis and factors promoting it favor Th17 differentiation as do environmental cues such as low oxygen levels, amino acid, and glucose abundance. Lipid oxidation on the other hand promotes Tregs generation. Fatty acids and metabolic cues linked to AMPK activation and poor mTOR activation (amino acid scarcity, lack of glucose metabolism) also promote Treg induction.