Inhibition of terminal differentiation of B cells mediated by CD27 and CD40 involves signaling through JNK.
B cells responding to cognate Ag in vivo undergo clonal expansion that is followed by differentiation into Ab-secreting plasma cells or into quiescent restimulable memory. Both these events occur in the germinal center and require that cells exit from proliferation, but the signals that lead to one or the other of these mutually exclusive differentiation pathways have not been definitively characterized. Previous experiments have shown that signals transduced through the TNFRs CD27 and CD40 at the time of B cell stimulation in vitro or in vivo can influence this cell fate decision by inhibiting terminal differentiation and promoting memory. In this study, we show that the PIQED domain of the cytoplasmic tail of murine CD27 and the adapter molecule TNFR-associated factor 2 are involved in this effect. Using pharmacological inhibitors of signaling intermediates, we identify JNK as being necessary and sufficient for the observed inhibition of terminal differentiation. While JNK is involved downstream of CD40, inhibition of the MEK pathway can also partially restore plasma cell generation, indicating that both signaling intermediates may be involved. We also show that inhibition of induction of IFN regulatory factor 4 and B lymphocyte induced maturation protein 1 are downstream events common to both receptors.
National Institute of Immunology, New Delhi, India.
Shuchismita
S
Satpathy
Gautam N
GN
Shenoy
Sheetal
S
Kaw
Tushar
T
Vaidya
Vineeta
V
Bal
Satyajit
S
Rath
Anna
A
George
D000818:Animals; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D006131:Growth Inhibitors / Q000502:physiology*; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D021381:Protein Transport / Q000276:immunology; D047992:TNF Receptor-Associated Factor 2; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology*; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000378:metabolism; D000099218:Interferon Regulatory Factor-4
D019013:CD40 Antigens; D006131:Growth Inhibitors; D050835:Interferon Regulatory Factors; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D000074462:Positive Regulatory Domain I-Binding Factor 1; D047992:TNF Receptor-Associated Factor 2; D014157:Transcription Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D000099218:Interferon Regulatory Factor-4; C101338:PSMD2 protein, human; C513258:Prdm1 protein, mouse