Effects of IL-9 on TRAF3-deficient B cell activation

Abstract The pleiotropic cytokine interleukin-9 (IL-9) signals to target cells by binding to a heterodimeric receptor consisting of the IL-9 receptor (IL-9R) and the common subunit γ chain. In the present study, we found that the expression of IL-9R was strikingly up-regulated in mouse naïve follicular B cells genetically deficient in TRAF3, a critical regulator of B cell survival and function. The highly up-regulated IL-9R on Traf3 −/−follicular B cells conferred responsiveness to IL-9, including IgM production and STAT3 phosphorylation. Interestingly, IL-9 significantly enhanced class switch recombination to IgG1 induced by B cell antigen receptor crosslinking plus IL-4 in Traf3 −/−B cells but not in wild type B cells. Blocking the JAK-STAT3 pathway abrogated the effects of IL-9 on Traf3 −/−B cells. Our study thus revealed a novel pathway that TRAF3 suppresses B cell activation and Ig isotype switching by inhibiting IL-9R-JAK-STAT3 signaling. Our findings provide new insights into the TRAF3-IL-9R axis in B cell function and have significant implications for the understanding and treatment of a variety of human diseases involving aberrant B cell activation. This study was supported by the National Institutes of Health grants R01 CA158402 (P. Xie) and R21 AI128264 (P. Xie), the Department of Defense grant W81XWH-13-1-0242 (P. Xie), and a Busch Biomedical Grant (P. Xie). FACS analyses were supported by the Flow Cytometry Core Facility with funding from NCI-CCSG P30CA072720.