Details

Autor(en) / Beteiligte

• Peng, Stanford L.
• Szabo, Susanne J.
• Glimcher, Laurie H.

Titel

T-bet Regulates IgG Class Switching and Pathogenic Autoantibody Production

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2002-04, Vol.99 (8), p.5545-5550

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2002

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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.