Regulatory T cells maintain long-term tolerance to myelin basic protein by inducing a novel, dynamic state of T cell tolerance.
The pathogenesis of multiple sclerosis involves a breakdown in T cell tolerance to myelin proteins like myelin basic protein (MBP). Most MBP-specific T cells are eliminated by central tolerance in adult mice, however, the developmentally regulated expression of MBP allows MBP-specific thymocytes in young mice to escape negative selection. It is not known how these T cells that encounter MBP for the first time in the periphery are regulated. We show that naive MBP-specific T cells transferred into T cell-deficient mice induce severe autoimmunity. Regulatory T cells prevent disease, however, suppression of the newly transferred MBP-specific T cells is abrogated by activating APCs in vivo. Without APC activation, MBP-specific T cells persist in the periphery of protected mice but do not become anergic, raising the question of how long-term tolerance can be maintained if APCs presenting endogenous MBP become activated. Our results demonstrate that regulatory T cells induce naive MBP-specific T cells responding to nonactivated APCs to differentiate into a unique, tolerized state with the ability to produce IL-10 and TGF-beta1 in response to activated, but not nonactivated, APCs presenting MBP. This tolerant response depends on continuous activity of regulatory T cells because, in their absence, these uniquely tolerized MBP-specific T cells can again induce autoimmunity.
Cabbage
Sarah E
SE
Molecular and Cellular Biology Program, Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Huseby
Eric S
ES
Sather
Blythe D
BD
Brabb
Thea
T
Liggitt
Denny
D
Goverman
Joan
J
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D049109:Cell Proliferation; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D017710:Lymphocyte Transfusion; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D004676:Myelin Basic Protein