TNF receptor-associated factor 3 restrains B-cell receptor signaling in normal and malignant B cells

Abstract

TRAF3 has diverse signaling functions, which vary by cell type. Uniquely in B lymphocytes, TRAF3 inhibits homeostatic survival. Highlighting the role of TRAF3 as a tumor suppressor, loss-of-function TRAF3 mutations are associated with human B-cell malignancies, while B-cell-specific deletion of TRAF3 in mice leads to autoimmunity and lymphoma development. The role of TRAF3 in inhibiting noncanonical NF-κB activation, CD40 and BAFF-R signaling to B cells is well documented. In contrast, TRAF3 enhances many T-cell effector functions, through associating with and enhancing signaling by the T-cell receptor (TCR)-CD28 complex. The present study was designed to determine the role of TRAF3 in signaling via the B-cell antigen receptor (BCR). The BCR is crucial for antigen recognition, survival, proliferation, and antibody production, and defects in BCR signaling can promote abnormal survival of malignant B cells. Here, we show that TRAF3 is associated with both CD79B and the BCR-activated kinases Syk and Btk following BCR stimulation. BCR-induced phosphorylation of Syk and additional downstream kinases was increased in TRAF3 −/− B cells, with regulation observed in both follicular and marginal zone B-cell subsets. BCR stimulation of TRAF3 −/− B cells resulted in increased surface expression of MHC-II, CD80, and CD86 molecules. Interestingly, increased survival of TRAF3 −/− primary B cells was resistant to inhibition of Btk, while TRAF3-deficient malignant B-cell lines showed enhanced sensitivity. TRAF3 serves to restrain normal and malignant BCR signaling, with important implications for its role in normal B-cell biology and abnormal survival of malignant B cells.

Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR

“…TRAF3 inhibits IL-2R signaling in T cells, promoting Treg differentiation ( 42 ), and suppresses signaling mediated by the IL-6R and the B cell antigen receptor in B cells ( 43 , 68 ). Signaling through IL-2 and IL-6 receptors is tightly regulated by TRAF3 recruited phosphatases, PTPN2 and PTPN22, respectively ( 39 ).…”

“…TRAF3 inhibits IL-2R signaling in T cells, promoting Treg differentiation (42), and suppresses signaling mediated by the IL-6R and the B cell antigen receptor in B cells (43,69).…”

Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B‐cell receptor signaling in mice

“…In this study, in vitro inhibition by ibrutinib resulted in reduced pSyk, even in Btk −/ − B cells [ 45 ], indicating an off‐target effect of ibrutinib. Very recently, BCR rewiring was also reported in a mouse model with B‐cell specific deletion of TNF receptor associated factor 3 (TRAF3); TRAF3‐deficient B cells showed increased BCR responsiveness in upstream signaling molecules, enhanced calcium influx, and pErk signaling upon BCR stimulation [ 46 ]. This is similar to our findings, although we did not observe increased calcium signaling.…”

Comparative studies on the structure, biological activity and molecular mechanisms of polysaccharides from Boletus aereus (BA-T) and Pleurotus cornucopiae (PC-1)

“…B cells were derived from the pluripotent stem cells of bone marrow, which could proliferate and differentiate into a large number of plasma cells when stimulated by antigens. Plasma cells could synthesize and secrete antibodies in the blood circulation, which plays an important role in the development and regulation of the immune system (Whillock et al, 2021). The results indicated that when the final mass concentration of polysaccharide was 2.5-20 μg/ml, the proliferation effect of B cells was enhanced.…”