Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells.
Proc Natl Acad Sci U S A
; 110(9): 3471-6, 2013 Feb 26.
Article
em En
| MEDLINE
| ID: mdl-23401506
ABSTRACT
Polymorphisms in MHC class II molecules, in particular around ß-chain position-57 (ß57), afford susceptibility/resistance to multiple autoimmune diseases, including type 1 diabetes, through obscure mechanisms. Here, we show that the antidiabetogenic MHC class II molecule I-A(b) affords diabetes resistance by promoting the differentiation of MHC-promiscuous autoreactive CD4(+) T cells into disease-suppressing natural regulatory T cells, in a ß56-67-regulated manner. We compared the tolerogenic and antidiabetogenic properties of CD11c promoter-driven transgenes encoding I-A(b) or a form of I-A(b) carrying residues 56-67 of I-Aß(g7) (I-A(b-g7)) in wild-type nonobese diabetic (NOD) mice, as well as NOD mice coexpressing a diabetogenic and I-A(g7)-restricted, but MHC-promiscuous T-cell receptor (4.1). Both I-A transgenes protected NOD and 4.1-NOD mice from diabetes. However, whereas I-A(b) induced 4.1-CD4(+) thymocyte deletion and 4.1-CD4(+)Foxp3(+) regulatory T-cell development, I-A(b-g7) promoted 4.1-CD4(+)Foxp3(+) Treg development without inducing clonal deletion. Furthermore, non-T-cell receptor transgenic NOD.CD11cP-I-A(b) and NOD.CD11cP-IA(b-g7) mice both exported regulatory T cells with superior antidiabetogenic properties than wild-type NOD mice. We propose that I-A(b), and possibly other protective MHC class II molecules, afford disease resistance by engaging a naturally occurring constellation of MHC-promiscuous autoreactive T-cell clonotypes, promoting their deviation into autoregulatory T cells.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antígenos de Histocompatibilidade Classe II
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Diferenciação Celular
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Linfócitos T Reguladores
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Diabetes Mellitus Experimental
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Fatores de Transcrição Forkhead
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article