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Gerth, AJ, Lin, L and Peng, SL (2003) T-bet regulates T-independent IgG2a class switching. Int. Immunol. 15:937-44
The IgG2a Ig subclass plays a critical role in the pathogenesis of humoral autoimmunity and protection against pathogens. The T-box transcription factor T-bet has been implicated as a critical mediator of class-switch recombination (CSR) to IgG2a, but its relative importance to this process in various immune contexts remains incompletely defined. We report here that, surprisingly, T-bet is selectively required for IgG2a class switching in response to T-independent, but not T-dependent, stimuli. Specifically, T-dependent signaling through CD40, in contrast to T-independent signaling via lipopolysaccharide, can bypass a requirement for T-bet in IgG2a germline transcription and subsequent isotype switching. In contrast, T-bet-deficient B cells undergo class switching to other IgG isotypes at least as well as wild-type counterparts. Thus, T-bet is a class-specific regulator of IgG CSR and represents a unique regulator of B cell differentiation by participating in a T-independent, but not a T-dependent, activation pathway. T-bet-deficient B cells therefore represent a novel paradigm by which to investigate the regulation of humoral immune responses.
Animals; Antigens, CD40/immunology; Antigens, CD40/pharmacology; Antigens, Differentiation, B-Lymphocyte/analysis; Antigens, T-Independent/immunology; Enzyme-Linked Immunosorbent Assay/methods; Ficoll/analogs & derivatives; Ficoll/immunology; Ficoll/pharmacology; Flow Cytometry/methods; Gene Expression Regulation; Haptens/immunology; Haptens/pharmacology; Immunization/methods; Immunoglobulin Class Switching/drug effects; Immunoglobulin Class Switching/immunology; Immunoglobulin G/genetics; Immunoglobulin G/immunology; Immunoglobulin Isotypes/blood; Immunoglobulin Isotypes/immunology; Interferon-gamma/immunology; Interferon-gamma/pharmacology; Lipopolysaccharides/immunology; Lipopolysaccharides/pharmacology; Lymphocyte Subsets/chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger/analysis; Reverse Transcriptase Polymerase Chain Reaction/methods; Spleen/cytology; T-Box Domain Proteins; Transcription Factors/genetics; Transcription Factors/immunology; Transcription Factors/physiology; Trinitrobenzenes/immunology; Trinitrobenzenes/pharmacology
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