Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity.
Nat Immunol, 2020/08;21(8):950-961.
Tanaka S[1, 2, 3], Ise W[1], Inoue T[1], Ito A[1], Ono C[2], Shima Y[4], Sakakibara S[5], Nakayama M[6], Fujii K[1], Miura I[7], Sharif J[8], Koseki H[8, 9], Koni PA[10], Raman I[11], Li QZ[11], Kubo M[3, 12], Fujiki K[13], Nakato R[13], Shirahige K[13], Araki H[14], Miura F[14], Ito T[14], Kawakami E[15, 16], Baba Y[17, 18], Kurosaki T[19, 20]
Affiliations
PMID: 32572241DOI: 10.1038/s41590-020-0700-y
Impact factor: 31.25
Abstract
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.
MeSH terms
Animals; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; B7-2 Antigen; DNA-Binding Proteins; Dioxygenases; Epigenesis, Genetic; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins
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