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TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis.

ABSTRACT: The low number of natural regulatory T cells (nTregs) in the circulation specific for a particular Ag and concerns about the bystander suppressive capacity of expanded nTregs presents a major clinical challenge for nTreg-based therapeutic treatment of autoimmune diseases. In the current study, we demonstrate that naive CD4+CD25-Foxp3- T cells specific for the myelin proteolipid protein (PLP)139-151 peptide can be converted into CD25+Foxp3+ induced Treg cells (iTregs) when stimulated in the presence of TGF-beta, retinoic acid, and IL-2. These PLP139-151-specific iTregs (139-iTregs) have a phenotype similar to nTregs, but additionally express an intermediate level of CD62L and a high level of CD103. Upon transfer into SJL/J mice, 139-iTregs undergo Ag-driven proliferation and are effective at suppressing induction of experimental autoimmune encephalomyelitis induced by the cognate PLP139-151 peptide, but not PLP178-191 or a mixture of the two peptides. Furthermore, 139-iTregs inhibit delayed-type hypersensitivity responses to PLP139-151, but not PLP178-191, myelin oligodendrocyte glycoprotein (MOG)35-55, or OVA323-339 in mice primed with a mixture of PLP139-151 and the other respective peptides. Additionally, 139-iTregs suppress the proliferation and activation of PLP139-151-, but not MOG35-55-specific CD4+ T cells in SJL/B6 F1 mice primed with a combination of PLP139-151 and MOG35-55. These findings suggest that Ag-specific iTregs are amplified in vivo when exposed to cognate Ag under inflammatory conditions, and these activated iTregs suppress CD4+ responder T cells in an Ag-specific manner.

SUBMITTER: Zhang H

PROVIDER: S-EPMC2882517 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis.

Zhang Hong H Podojil Joseph R JR Chang Judy J Luo Xunrong X Miller Stephen D SD

Journal of immunology (Baltimore, Md. : 1950) 20100507 12

The low number of natural regulatory T cells (nTregs) in the circulation specific for a particular Ag and concerns about the bystander suppressive capacity of expanded nTregs presents a major clinical challenge for nTreg-based therapeutic treatment of autoimmune diseases. In the current study, we demonstrate that naive CD4+CD25-Foxp3- T cells specific for the myelin proteolipid protein (PLP)139-151 peptide can be converted into CD25+Foxp3+ induced Treg cells (iTregs) when stimulated in the prese ...[more]

PMID: 20483764

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Project description:IntroductionMultiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Ursolic acid (UA) can be used in the MS treatment with anti-inflammatory and neuroprotective activities. However, UA is insoluble in water, which may affect its medication effectiveness. In our previous study, UAOS-Na, a water-soluble derivative of UA was obtained. In this study, we evaluated the pharmacological effects and explored its underlying mechanism of UAOS-Na on experimental autoimmune encephalomyelitis (EAE).MethodsFirstly, the pharmacodynamics of UAOS-Na was investigated in EAE and Cuprizone-induced mice. And then the possible mechanisms were investigated by TMT proteomics and verified by in vitro and in vivo experiments.ResultsUAOS-Na (30 mg/kg/d) delayed the onset time of EAE from 11.78 days post immunization (dpi) to 14.33 dpi, reduced the incidence from 90.0% to 42.9%. UAOS-Na (60 mg/kg/d) reduced the serum levels of IFN-γ, IL-17A, TNF-α and IL-6, reduced the mononuclear cell infiltration of spinal cord, and inhibited the overexpression of key transcription factors T-bet and ROR-γt of EAE mouse spinal cord. In addition, UAOS-Na attenuated demyelination and astrogliosis in the CNS of EAE and cuprizone-induced mice. Mechanistically, proteomics showed that 96 differential expression proteins (DEPs) were enriched and 94 were upregulated in EAE mice compared with normal group. After UAOS-Na treatment, 16 DEPs were enriched and 15 were downregulated, and these DEPs were markedly enriched in antigen processing and presentation (APP) signaling pathway. Moreover, UAOS-Na downregulated the protein levels of Tapbp and H2-T23 in MHC-I antigen presentation pathway and reduced the proliferation of splenic CD8 T cells, thereby inhibiting the CNS infiltration of CD8 T cells.ConclusionOur findings demonstrated that UAOS-Na has both myelin protective and anti-inflammatory effects. And it could reduce the inflammation of MS by downregulating the expression of Tapbp and H2-T23 in the MHC-I antigen presentation pathway.

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TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis.

Publications

TGF-beta-induced myelin peptide-specific regulatory T cells mediate antigen-specific suppression of induction of experimental autoimmune encephalomyelitis.

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