Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor.
This manuscript systematically identifies the molecular mechanisms that regulate the ability of B cells to produce the critical type 1 cytokine, IFN-gamma. B cells produce IFN-gamma in response to IL-12 and IL-18 and when primed by Th1 cells. We show that development of IFN-gamma-producing B cells by either Th1 cells or IL-12/IL-18 is absolutely dependent on expression of the IFN-gammaR and the T-box transcription factor, T-bet. Interestingly, although T-bet up-regulation in developing B effector 1 (Be1) cells is controlled by IFN-gammaR-mediated signals, STAT1-deficient B cells up-regulate T-bet and produce IFN-gamma, indicating that additional transcriptional activators must be coupled to the IFN-gammaR in B cells. Finally, we show that although IL-12/IL-18 or IFN-gamma-producing Th1 cells are required to initiate transcription of the IFN-gamma gene in B cells, sustained expression of IFN-gamma and T-bet by B cells is dependent on an IFN-gamma/IFN-gammaR/T-bet autocrine feedback loop. These findings have significant implications, because they suggest that IFN-gamma-producing B cells not only amplify Th1 responses, but also imprint a type 1 phenotype on B cells themselves. In the case of immune responses to bacterial or viral pathogens, this B cell-driven autocrine feedback loop is likely to be beneficial; however, in the case of B cell responses to autoantigens, it may result in amplification of the autoimmune loop and increased pathology.
Harris
David P
DP
Trudeau Institute, Saranac Lake, NY 12983, USA.
Goodrich
Stephen
S
Gerth
Andrea J
AJ
Peng
Stanford L
SL
Lund
Frances E
FE
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000378:metabolism*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor; C494080:Stat1 protein, mouse; C494091:Stat4 protein, mouse