Opposing Roles for TRAF1 in the Alternative versus Classical NF-κB Pathway in T Cells

Abstract

Background: The T cell costimulatory molecule 4-1BB signals through TRAF1 and TRAF2. Results: TRAF1Ϫ/Ϫ T cells show hyperproliferation due to enhanced alternative NF-B activation but have impaired classical

T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63–Polyubiquitin-Dependent Signals from Endosomes

“…The involvement of TRAF2 and TRAF1 in the activation of NFkB and MAPK by CD137 has been previously shown (37,63). Our results illustrate that there exists a CD137 signaling pathway dependent on K63-linked polyubiquitination of substrates, including TRAF2, which is critical for CD137 biological functions.…”

“…CD137 signaling has been shown to involve TRAF2 (19-21) and TRAF1 complexes (37,38). In fact, TRAF2 KO mice signal FIGURE 4.…”

“…However, there was a significant delay (of ∼1 wk) in the rejection of CT26 tumors induced by CD137 mAb treatment in Traf2DN-tg mice when compared with that of WT littermates. Because CD137-mediated tumor rejection was delayed but still achieved in mice functionally deficient for TRAF2, other proteins, particularly other TRAF family members such as TRAF1 (20,37) or even TRAF5, that could substitute TRAF2 in regulating signaling from certain TNFR family members (49) might also participate in CD137-mediated tumor rejection. Of note is that both the Traf2DN-tg mice and WT littermates, which attained complete rejection upon treatment with anti-CD137 mAb, were able to efficiently reject a second inoculation of CT26 cells performed 2 mo later, thus indicating that TRAF2 does not seem to be required to render tumor-protective T cell memory in mice that had previously rejected a tumor upon anti-CD137 mAb therapy (data not shown).…”

Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers

“…Thus, the induction of TNFR2 expression in CD8 + T cells is bimodal as its expression induced via TCR signaling is further up-regulated upon 4-1BB signaling induced by 4BL cells. Since 4-1BB can signal via both the canonical and non-canonical NF-κB pathway (52), we also compared the induction of TNFR2 in CD8 + T cells from mice deficient in classical (p50) and non-canonical (p52) NF-κB. While 4BL cells in the presence of anti-CD3 Ab up-regulated TNFR2 in p50 KO CD8 + T cells as efficiently as in WT T cells (Fig.…”

Activation-induced Tumor Necrosis Factor Receptor-associated Factor 3 (Traf3) Alternative Splicing Controls the Noncanonical Nuclear Factor κB Pathway and Chemokine Expression in Human T Cells

“…Degradation of Traf3 itself, e.g. upon stimulation of CD40 or BAFF receptors in B cells, or 4-1BB in T cells, separates NIK from Traf2-cIAP thus allowing accumulation of NIK to initiate ncNFB signaling (22,26). A further regulatory layer is added through the control of receptor-induced Traf3 degradation by the deubiquitinase OTUD7B, underlining the necessity of tightly controlled Traf3 expression and ncNFB signaling for proper immune function (27).…”