Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Differentiation, B-Lymphocyte / analysis
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Antigens, T-Independent / immunology*
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CD40 Antigens / immunology
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CD40 Antigens / pharmacology
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Enzyme-Linked Immunosorbent Assay / methods
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Ficoll / analogs & derivatives*
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Ficoll / immunology
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Ficoll / pharmacology
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Flow Cytometry / methods
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Gene Expression Regulation
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Haptens / immunology
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Haptens / pharmacology
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Immunization / methods
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Immunoglobulin Class Switching / drug effects
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Immunoglobulin Class Switching / immunology*
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology*
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Immunoglobulin Isotypes / blood
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Immunoglobulin Isotypes / immunology
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Interferon-gamma / immunology
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Interferon-gamma / pharmacology
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Lipopolysaccharides / immunology
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Lipopolysaccharides / pharmacology
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Lymphocyte Subsets / chemistry
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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RNA, Messenger / analysis
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Spleen / cytology
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T-Box Domain Proteins
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transcription Factors / physiology*
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Trinitrobenzenes / immunology
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Trinitrobenzenes / pharmacology
Substances
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Antigens, Differentiation, B-Lymphocyte
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Antigens, T-Independent
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CD40 Antigens
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Haptens
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Immunoglobulin G
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Immunoglobulin Isotypes
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Lipopolysaccharides
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RNA, Messenger
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T-Box Domain Proteins
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T-box transcription factor TBX21
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TNP-ficoll
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Transcription Factors
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Trinitrobenzenes
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trinitrophenyl-lipopolysaccharide
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Ficoll
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Interferon-gamma