A role for IRF8 in B cell anergy.
B cell central tolerance is a process through which self-reactive B cells are removed from the B cell repertoire. Self-reactive B cells are generally removed by receptor editing in the bone marrow and by anergy induction in the periphery. IRF8 is a critical transcriptional regulator of immune system development and function. A recent study showed that marginal zone B cell and B1 B cell populations are dramatically increased in IRF8-deficient mice, indicating that there are B cell-developmental defects in the absence of IRF8. In this article, we report that mice deficient for IRF8 produced anti-dsDNA Abs. Using a hen egg lysozyme double-transgenic model, we further demonstrate that B cell anergy was breached in IRF8-deficient mice. Although anergic B cells in the IRF8-proficient background were blocked at the transitional stage of development, anergic B cells in the IRF8-deficient background were able to mature further, which allowed them to regain responses to Ag stimulation. Interestingly, our results show that IRF8-deficient B cells were more sensitive to Ag stimulation and were resistant to Ag-induced cell death. Moreover, our results show that IRF8 was expressed at a high level in the anergic B cells, and an elevated level of IRF8 promoted apoptosis in the transitional B cells. Thus, our findings reveal a previously unrecognized function of IRF8 in B cell anergy induction.
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198.
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D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D015478:Antigens, Heterophile / Q000276:immunology; D017209:Apoptosis; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology*; D004247:DNA / Q000276:immunology; D005838:Genotype; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation; D038041:Lymphopoiesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
D000974:Antibodies, Antinuclear; D015478:Antigens, Heterophile; D004247:DNA; D050835:Interferon Regulatory Factors; D009113:Muramidase; D011947:Receptors, Antigen, B-Cell; D011993:Recombinant Fusion Proteins; D000099185:Interferon Regulatory Factor-8