Impaired T cell-Independent antibody responses and mucosal IgA production in Traf5-deficient mice

Tumor necrosis factor receptor-associated factor 5 (TRAF5) is an adaptor protein that mediates signaling downstream of multiple immunoregulatory receptors, including members of the tumor necrosis factor receptor superfamily. Although TRAF5 has been implicated in B-cell activation during T-cell-dependent humoral immune responses, its role in B-cell responses to a proliferation-inducing ligand (APRIL; TNFSF13) and T-cell-independent type 2 (TI-2) antibody responses remains poorly defined. Here, we show that Traf5 deficiency impairs antigen-specific IgG3 production during TI-2 immune responses and reduces fecal IgA levels. Traf5 -deficient mice exhibited markedly reduced IgG3 responses to the TI-2 antigen 2,4,6-trinitrophenyl-conjugated Ficoll, whereas antigen-specific IgM production was preserved. In addition, Traf5 deficiency resulted in significantly decreased fecal IgA levels and reduced density of IgA + cells in the colonic lamina propria, whereas the frequencies of IgA + B cells in Peyer’s patches and the small intestine remained largely unchanged. T-cell and B-cell development was comparable between wild-type and Traf5 -deficient mice. Although the expression of the APRIL receptor transmembrane activator and CAML interactor (TACI; TNFRSF13B) on splenic B cells was comparable between wild-type and Traf5 -deficient mice, APRIL-induced expression of activation-induced cytidine deaminase (AID; encoded by Aicda ) and IgA production in vitro were selectively impaired in Traf5 -deficient splenic B cells, without affecting B-cell survival. Collectively, these findings indicate that TRAF5 contributes to optimal TI-2 immune responses and is associated with mucosal IgA production. The impaired APRIL-induced Aicda expression and IgA production observed in Traf5 -deficient splenic B cells suggest that TRAF5 contributes to T-cell-independent humoral immunity.