IL-17A deficiency in HLA-DR3 transgenic mice enriches beneficial Prevotella species in gut to promote Tregs and reduce CNS autoimmunity

Abstract Background Human Leukocyte Antigen (HLA) class-II genes, particularly HLA-DR2 and HLA-DR3, and the gut microbiota are intricately linked to the pathobiology of multiple sclerosis (MS) through their ability to regulate host immunity, a critical factor in disease pathogenesis. An imbalance between anti-inflammatory CD4 + Tregs and pro-inflammatory IL-17A-secreting CD4 + Th17 cells is thought to drive disease. However, a key unresolved question is whether HLA-class II-restricted CD4 + IL-17A cells can influence Treg populations and the extent to which gut microbiota regulate this IL-17A-Treg axis. Therefore, we utilized humanized transgenic mice expressing the HLA class-II gene and deficient in mouse class-II molecules, where all CD4 + T cells are selected on the human HLA class-II molecule, closely mimicking human immune responses. Results Utilizing IL-17A-deficient (DR3.IL-17A −/− ) mice expressing HLA-DR3 (HLA-DRβ1*0301), we show that IL-17A deficiency enriches beneficial gut bacteria, including Prevotella species , enhances peroxisome proliferator–activated receptor (PPAR) signaling, and increases FoxP3 + regulatory T (Treg) cells and IL-10 production. The importance of gut microbiota in promoting Tregs and anti-inflammatory responses was confirmed by administering Prevotella copri , a common commensal in human gut, which mirrored the effects observed in IL-17A-deficient mice by inducing PPAR signaling and Treg population. Moreover, DR3.IL-17A −/− mice exhibited a marked reduction in EAE severity compared to IL-17A-sufficient (DR3) mice, underscoring the enhanced functional capacity of the Treg population in mitigating disease progression. Cohousing experiments validated the role of gut microbiota in immune regulation including Treg induction, as demonstrated by the transfer of Prevotella species from IL-17A-deficient mice to IL-17A-sufficient mice, increased Treg populations and attenuated EAE severity in recipient DR3 mice. Conclusions This study redefines IL-17A's role in immune regulation, emphasizing its ability to directly influence gut microbiota composition and the abundance of Treg-promoting bacteria. Thus, gut microbiota-targeted therapies, particularly those promoting Treg-inducing bacteria like Prevotella species , hold promise for treating autoimmune diseases by modulating host immune responses.