Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity.

Animals Autoimmune Diseases / immunology Autoimmunity / immunology B-Lymphocytes / immunology B7-2 Antigen / immunology DNA-Binding Proteins / immunology Dioxygenases / immunology Epigenesis, Genetic / immunology Lymphocyte Activation / immunology Mice Mice, Inbred C57BL Mice, Transgenic Proto-Oncogene Proteins / immunology

Journal

Nature immunology

ISSN: 1529-2916

Titre abrégé: Nat Immunol

Pays: United States

ID NLM: 100941354

Informations de publication

Date de publication:
08 2020

Historique:

received: 30 08 2019

accepted: 04 05 2020

pubmed: 24 6 2020

medline: 5 11 2020

entrez: 24 6 2020

Statut: ppublish

Résumé

A contribution of epigenetic modifications to B cell tolerance has been proposed but not directly tested. Here we report that deficiency of ten-eleven translocation (Tet) DNA demethylase family members Tet2 and Tet3 in B cells led to hyperactivation of B and T cells, autoantibody production and lupus-like disease in mice. Mechanistically, in the absence of Tet2 and Tet3, downregulation of CD86, which normally occurs following chronic exposure of self-reactive B cells to self-antigen, did not take place. The importance of dysregulated CD86 expression in Tet2- and Tet3-deficient B cells was further demonstrated by the restriction, albeit not complete, on aberrant T and B cell activation following anti-CD86 blockade. Tet2- and Tet3-deficient B cells had decreased accumulation of histone deacetylase 1 (HDAC1) and HDAC2 at the Cd86 locus. Thus, our findings suggest that Tet2- and Tet3-mediated chromatin modification participates in repression of CD86 on chronically stimulated self-reactive B cells, which contributes, at least in part, to preventing autoimmunity.

Identifiants

DOI: 10.1038/s41590-020-0700-y PMID: 32572241

pubmed: 32572241

doi: 10.1038/s41590-020-0700-y

pii: 10.1038/s41590-020-0700-y

doi:

Substances chimiques

B7-2 Antigen 0

Cd86 protein, mouse 0

DNA-Binding Proteins 0

Proto-Oncogene Proteins 0

Dioxygenases EC 1.13.11.-

Tet2 protein, mouse EC 1.13.11.-

Tet3 protein, mouse EC 1.13.11.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

950-961

Commentaires et corrections

Type : ErratumIn

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