The binding site for TRAF2 and TRAF3 but not for TRAF6 is essential for CD40-mediated immunoglobulin class switching.
To define the role of TRAF proteins in CD40-dependent isotype switching in B cells, we introduced wild-type (WT) and mutant CD40 transgenes that lacked the binding motifs for TRAF6 (CD40deltaTRAF6), TRAF2 and TRAF3 (CD40deltaTRAF2/3), or both (CD40deltaTRAFs) into B cells of CD40(-/-) mice. The in vivo isotype switch defect in CD40(-/-) mice was fully corrected by WT and CD40deltaTRAF6, partially by CD40deltaTRAF2/3, and not at all by CD40deltaTRAFs transgenes. CD40-mediated isotype switching, proliferation, and activation of p38, JNK, and NFkappaB in B cells were normal in WT and CD40deltaTRAF6 mice, severely impaired in CD40deltaTRAF2/3, and absent in CD40deltaTRAFs mice. These results suggest that binding to TRAF2 and/or TRAF3 but not TRAF6 is essential for CD40 isotype switching and activation in B cells.
D020816:Amino Acid Motifs; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D005816:Genetic Complementation Test; D018858:Germinal Center / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D007136:Immunoglobulins / Q000096:biosynthesis / Q000097:blood; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D015854:Up-Regulation
D015703:Antigens, CD; D019013:CD40 Antigens; D007136:Immunoglobulins; D016328:NF-kappa B; D011506:Proteins; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin