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.