T-bet regulates IgG class switching and pathogenic autoantibody production.
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-gamma. 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-gamma-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-gamma-mediated IgG2a class switching in B cells and emphasize the importance of this regulation in the pathogenesis of humorally mediated autoimmunity.
Peng
Stanford L
SL
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115-6017, USA.
Szabo
Susanne J
SJ
Glimcher
Laurie H
LH
D000818:Animals; D001323:Autoantibodies / Q000737:chemistry*; D015551:Autoimmunity / Q000502:physiology*; D001402:B-Lymphocytes / Q000378:metabolism; D015704:CD4 Antigens / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000737:chemistry*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism*; D008177:Lupus Vulgaris / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000276:immunology / Q000502:physiology*; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
D001323:Autoantibodies; D015704:CD4 Antigens; D007074:Immunoglobulin G; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D015847:Interleukin-4; D007371:Interferon-gamma