T-bet regulates T-independent IgG2a class switching.
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.
Gerth
Andrea J
AJ
Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Lin
Ling
L
Peng
Stanford L
SL
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D000955:Antigens, T-Independent / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005362:Ficoll / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation; D006241:Haptens / Q000276:immunology / Q000494:pharmacology; D007114:Immunization / Q000379:methods; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D016131:Lymphocyte Subsets / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000166:cytology; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014301:Trinitrobenzenes / Q000276:immunology / Q000494:pharmacology; D000098815:T-bet Transcription Factor
D000944:Antigens, Differentiation, B-Lymphocyte; D000955:Antigens, T-Independent; D019013:CD40 Antigens; D006241:Haptens; D007074:Immunoglobulin G; D007132:Immunoglobulin Isotypes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C020529:TNP-ficoll; D014157:Transcription Factors; D014301:Trinitrobenzenes; C048761:trinitrophenyl-lipopolysaccharide; D005362:Ficoll; D007371:Interferon-gamma