title: NFATc2 (NFAT1) assists BCR-mediated anergy in anti-insulin B cells.
abstract: NFAT transcription factors play critical roles in both the activation and repression of T and B lymphocyte responses. To understand the role of NFATc2 (NFAT1) in the maintenance of tolerance for anti-insulin B cells, functionally inactive NFATc2 (NFATc2(-/-)) was introduced into C57BL/6 mice that harbor anergic anti-insulin 125Tg B cells. The production and peripheral maturation of anti-insulin B cells into follicular and marginal zone subsets was not altered by the absence of functional NFATc2. Surface B cell receptor expression levels, important for tonic signaling and altered by anergy, were not altered in any spleen B cell subset. The levels of anti-insulin antibodies were not different in 125Tg/B6/NFATc2(-/-) mice and the anti-insulin response remained silenced following T cell dependent immunization. However, studies addressing in vitro proliferation reveal the anergic state of 125Tg B cells is relieved in 125Tg/B6/NFATc2(-/-) B cells in response to BCR stimulation. In contrast, anergy is not released in 125Tg/B6/NFATc2(-/-) B cells following stimulation with anti-CD40. The relief of anergy to BCR stimulation in 125Tg/B6/NFATc2(-/-) B cells is associated with increased transcription of both NFATc1 and NFATc3 while expression of these NFATs does not change in anti-IgM stimulated 125Tg/B6/NFATc2(+/+) B cells. The data suggest that NFATc2 plays a subtle and selective role in maintaining anergy for BCR stimulation by repressing the transcription of other NFAT family members.
authors: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, MCN T3113, 21st Avenue S., Nashville, TN 37232, USA.
authors: Rachel H
authors: RH
authors: Bonami
authors: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, MCN T3113, 21st Avenue S., Nashville, TN 37232, USA.
authors: William T
authors: WT
authors: Wolfle
authors: Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University, MCN T3113, 21st Avenue S., Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, MCN T3113, 21st Avenue S., Nashville, TN 37232, USA. Electronic address: james.w.thomas@vanderbilt.edu.
authors: James W
authors: JW
authors: Thomas
authors: Department of Pathology, Microbiology, and Immunology, Vanderbilt University, MCN T3113, 21st Avenue S., Nashville, TN 37232, USA; Division of Allergy, Pulmonary, and Critical Care, Department of Medicine, Vanderbilt University, MCN T3113, 21st Avenue S., Nashville, TN 37232, USA.
authors: Peggy L
authors: PL
authors: Kendall
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D002478:Cells, Cultured; D007108:Immune Tolerance / Q000276:immunology; D007328:Insulin; D007330:Insulin Antibodies / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D007328:Insulin; D007330:Insulin Antibodies; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D011947:Receptors, Antigen, B-Cell
keywords: Autoimmunity; B cell; Insulin; NFAT; Signaling; Tolerance