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.
© 2012 British Society for Immunology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoimmune Diseases / immunology
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Autoimmunity / drug effects
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Autoimmunity / immunology
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Bacillus / immunology
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Bacillus / metabolism
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Cell Differentiation / drug effects*
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Cell Differentiation / immunology
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism
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Encephalomyelitis, Autoimmune, Experimental / therapy*
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Female
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Flow Cytometry
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Forkhead Transcription Factors / immunology
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Forkhead Transcription Factors / metabolism
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Interleukin-17 / immunology
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Interleukin-17 / metabolism
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Myeloid Differentiation Factor 88 / immunology
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Myeloid Differentiation Factor 88 / metabolism
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Polyglutamic Acid / administration & dosage
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Polyglutamic Acid / analogs & derivatives*
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Polyglutamic Acid / immunology
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Receptors, Retinoic Acid / antagonists & inhibitors
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Receptors, Retinoic Acid / immunology
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Receptors, Retinoic Acid / metabolism
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / agonists
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Suppressor of Cytokine Signaling Proteins / immunology
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Suppressor of Cytokine Signaling Proteins / metabolism
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T-Lymphocytes, Regulatory / drug effects*
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T-Lymphocytes, Regulatory / immunology
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Th17 Cells / drug effects*
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Th17 Cells / immunology
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Toll-Like Receptor 3 / immunology
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Toll-Like Receptor 3 / metabolism
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism
Substances
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-17
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Interleukin-6
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Retinoic Acid
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STAT3 Transcription Factor
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Socs3 protein, mouse
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Stat3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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TLR3 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Transforming Growth Factor beta
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poly(gamma-glutamic acid)
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Polyglutamic Acid