Search

A disrupted equilibrium between IL-17A-producing CD4 T-cells (Th17) and CD4+CD25+FoxP3+ regulatory T cells (Tregs) play an important role in the pathobiology of Multiple sclerosis (MS). Gut bacteria help in maintaining immune homeostasis by regulating the balance between anti-inflammatory Tregs and pro-inflammatory Th17 cells. Although, both gut bacteria and Tregs can regulate Th17 cells, the impact of IL-17A on gut microbiota and Tregs is unclear. Utilizing HLA-DR3 transgenic mouse model of MS, we show that IL-17A deficiency (HLA-DR3.IL17A-/- mice) expands Treg-inducing gut bacteria such as Prevotella, Parabacteroides, and Bacteroides and consequently Tregs, resulting in a milder disease in an animal model of MS. Notably, IL-17A sufficient DR3 mice develop milder disease on cohousing with IL-17A-deficient mice, highlighting a dominant role for gut microbiota in inducing Treg and reducing disease severity. Further, we observed an enrichment of bacterial-specific Treg promoting short-chain-fatty-acid metabolic pathways and induction of tolerogenic dendritic cells in HLA-DR3.IL17A-/- mice. Thus, our study shows a novel role of IL-17A in immune homeostasis and inflammation through regulation of the gut microbiota-Treg axis which can be used for the development of gut bacteria as therapeutics for MS.Significance of our workIL-17A a pro-inflammatory cytokine, is linked with pathobiology of multiple inflammatory diseases including multiple sclerosis (MS) and regulated by both gut microbiota and regulatory CD4 T cells (Tregs). However, the importance of IL-17A in the regulation of gut microbiota and Treg is unknown. Here we show that IL-17A can regulate Treg and disease phenotype by modulating gut microbiota and provide a novel mechanism by which immune-mediators such as IL-17A impact the gut microbiota to alter immune cell function and ultimately disease outcomes. Transfer of milder disease phenotype from IL-17A deficient mice to IL-17A sufficient mice on cohousing indicate a dominant role of gut microbiota in disease suppression. Thus, our study lays the foundation for future studies to unravel the interplay between immunological responses and the gut microbiota which will result in the development of microbiota-based therapeutics to treat autoimmune diseases.

SUMMARYAntigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate for de novo purine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2 in vivo reduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.