T-bet regulates IgG class switching and pathogenic autoantibody production

SL Peng, SJ Szabo… - Proceedings of the …, 2002 - National Acad Sciences
SL Peng, SJ Szabo, LH Glimcher
Proceedings of the National Academy of Sciences, 2002National Acad Sciences
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 …
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.
National Acad Sciences