Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells.
Stat proteins are latent cytoplasmic transcription factors that are crucial in many aspects of mammalian development. In the immune system, Stat3 has distinct roles in T-cell, neutrophil, and macrophage function, but a role for Stat3 in B-cell development, particularly in the terminal differentiation of B cells into antibody-secreting plasma cells, has never been directly tested. In this study, we used the Cre/lox system to generate a mouse strain in which Stat3 was conditionally deleted in the B-cell lineage (Stat3(fl/fl)CD19(Cre/+)). B-cell development, establishment of the peripheral B-cell compartment, and baseline serum antibody levels were unperturbed in Stat3(fl/fl)CD19(Cre/+) mice. Strikingly, Stat3(fl/fl)CD19(Cre/+) mice displayed profound defects in T-dependent (TD) IgG responses, but normal TD IgM, IgE, and IgA responses and T-independent (TI) IgM and IgG3 responses. In addition, germinal center (GC) formation, isotype switching, and generation of memory B cells, including IgG+ memory cells, were all intact in Stat3(fl/fl)CD19(Cre/+) mice, indicating that the requirement for Stat3 was limited to plasma cell differentiation. These results demonstrate a profound yet highly selective role for Stat3 in TD IgG plasma cell differentiation, and therefore represent a unique example of a transcription factor regulating isotype-specific terminal B-cell differentiation.
Fornek
Jamie L
JL
Department of Microbiology-Immunology, Feinberg School of Medicine of Northwestern University, Chicago, IL 60611, USA.
Tygrett
Lorraine T
LT
Waldschmidt
Thomas J
TJ
Poli
Valeria
V
Rickert
Robert C
RC
Kansas
Geoffrey S
GS
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D019426:Integrases / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics
D018941:Antigens, CD19; D007132:Immunoglobulin Isotypes; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases