title: 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.
authors.affiliation: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.forename: Judy
authors.initials: J
authors.lastname: Chang
authors.forename: Xunrong
authors.initials: X
authors.lastname: Luo
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D002469:Cell Separation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006023:Glycoproteins / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000276:immunology; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; C445081:myelin oligodendrocyte glycoprotein (35-55); C435023:myelin proteolipid protein (139-151)