T-bet Regulates IgG Class Switching and Pathogenic Autoantibody Production

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-04, Vol.99 (8), p.5545-5550
• Main Authors: Peng, Stanford L., Szabo, Susanne J., Glimcher, Laurie H.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Autoantibodies; Autoantibodies - chemistry; Autoimmunity; Autoimmunity - physiology; B lymphocytes; B-Lymphocytes - metabolism; Biological Sciences; CD4 Antigens - chemistry; CD4-Positive T-Lymphocytes - metabolism; Enzyme-Linked Immunosorbent Assay; g-Interferon; Genotypes; Germ cells; Immunoglobulin Class Switching; Immunoglobulin G - chemistry; Interferon-gamma - metabolism; Interleukin-4 - metabolism; Isotypes; Lupus; Lupus Vulgaris - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Plasmids; Plasmids - metabolism; Polymerase Chain Reaction; RNA, Messenger - metabolism; T lymphocytes; T-bet protein; T-Box Domain Proteins; T-Lymphocytes - metabolism; Time Factors; Transcription Factors - immunology; Transcription Factors - physiology; Transcription, Genetic
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.082114899

A molecular understanding of the regulation of IgG class switching to IL-4-independent isotypes, particularly to IgG2a, remains largely unknown. The T-box transcription factor T-bet directly regulates Th1 lineage commitment by CD4 T cells, but its role in B lymphocytes has been largely unexplored. We show here a role for T-bet in the regulation of IgG class switching, especially to IgG2a. T-bet-deficient B lymphocytes demonstrate impaired production of IgG2a, IgG2b, and IgG3 and, most strikingly, are unable to generate germ-line or postswitch IgG2a transcripts in response to IFN-γ. Conversely, enforced expression of T-bet initiates IgG2a switching in cell lines and primary cells. This function contributes critically to the pathogenesis of murine lupus, where the absence of T-bet strikingly reduces B cell-dependent manifestations, including autoantibody production, hypergammaglobulinemia, and immune-complex renal disease and, in particular, abrogates IFN-γ-mediated IgG2a production. Classical T cell manifestations persisted, including lymphadenopathy and cellular infiltrates of skin and liver. These results identify T-bet as a selective transducer of IFN-γ-mediated IgG2a class switching in B cells and emphasize the importance of this regulation in the pathogenesis of humorally mediated autoimmunity.