title: Bacillus-derived poly-γ-glutamic acid reciprocally regulates the differentiation of T helper 17 and regulatory T cells and attenuates experimental autoimmune encephalomyelitis.
abstract: Forkhead box protein 3 (FoxP3(+)) regulatory T (T(reg)) 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-γ-glutamic acid (γ-PGA) signals naive CD4(+) T cells to promote the selective differentiation of T(reg) cells and to suppress the differentiation of Th17 cells. The γ-PGA inducibility of FoxP3 expression was due partially to transforming growth factor (TGF)-β induction through a Toll-like receptor (TLR)-4/myeloid differentiating factor 88 (MyD88)-dependent pathway. However, this pathway was dispensable for γ-PGA suppression of Th17 differentiation. γ-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 γt (RORγt) while up-regulating the STAT-3 inhibitor suppressor of cytokine signalling 3 (SOCS3). Importantly, in vivo administration of γ-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, γ-PGA, as a novel regulator of autoimmune responses, capable of promoting the differentiation of anti-inflammatory T(reg) cells and suppressing the differentiation of proinflammatory Th17 cells. These findings draw attention to the potential of γ-PGA for treating Th17 cell-mediated autoimmune diseases.
authors.affiliation: Department of Anatomy & Cell Biology, College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Hwang
authors.forename: D J
authors.initials: DJ
authors.lastname: Paik
authors.forename: W K
authors.initials: WK
authors.lastname: Kim
authors.forename: J M
authors.initials: JM
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: Youn
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D001407:Bacillus / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D011099:Polyglutamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D011099:Polyglutamic Acid; D018168:Receptors, Retinoic Acid; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D000093242:Interleukin-6 Inhibitors; C498833:Foxp3 protein, mouse; C507780:Myd88 protein, mouse; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; C511775:poly(gamma-glutamic acid)