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Bacillus-derived poly–glutamic acid reciprocally regulates the differentiation of T helper 17 and regulatory T cells and attenuates experimental autoimmune encephalomyelitis

Lee, K;Hwang, S;Paik, DJ;Kim, WK;Kim, JM;Youn, J;

Forkhead box protein 3 (FoxP3+) regulatory T (Treg) cells and interleukin (IL)-17-producing T helper 17 (Th17) cells have opposing effects on autoimmunity, as the former are crucial for maintaining self-tolerance while the latter play a key role in precipitating inflammatory autoimmune diseases. Here we report that Bacillus-derived poly--glutamic acid (-PGA) signals naive CD4+ T cells to promote the selective differentiation of Treg cells and to suppress the differentiation of Th17 cells. The -PGA inducibility of FoxP3 expression was due partially to transforming growth factor (TGF)- induction through a Toll-like receptor (TLR)-4/myeloid differentiating factor 88 (MyD88)-dependent pathway. However, this pathway was dispensable for -PGA suppression of Th17 differentiation. -PGA inhibited IL-6-driven induction of Th17-specific factors including signal transducer and activator of transcription-3 (STAT-3) and retinoic acid-related orphan receptor t (RORt) while up-regulating the STAT-3 inhibitor suppressor of cytokine signalling 3 (SOCS3). Importantly, in vivo administration of -PGA attenuated the symptoms of experimental autoimmune encephalomyelitis and at the same time reduced Th17 cell infiltrates in the central nervous system. Thus, we have identified the microbe-associated molecular pattern, -PGA, as a novel regulator of autoimmune responses, capable of promoting the differentiation of anti-inflammatory Treg cells and suppressing the differentiation of proinflammatory Th17 cells. These findings draw attention to the potential of -PGA for treating Th17 cell-mediated autoimmune diseases.