Leukocyte-specific protein 1 links TNF receptor-associated factor 1 to survival signaling downstream of 4-1BB in T cells

Abstract

4-1BB is a member of the TNFR superfamily, which contributes to the activation of signaling pathways required for the survival of activated and memory T cells. We have shown previously that TRAF1, an adaptor protein recruited to 4-1BB, is required for 4-1BB-mediated CD8 T cell survival in vivo. With the use of a proteomics approach in primary T cells, we have identified LSP1 as a novel protein recruited to the 4-1BB signaling complex in a TRAF1-dependent manner. Further characterization of the interaction between TRAF1 and LSP1 revealed that LSP1 requires the TRAF-N domain of TRAF1 for direct association. Similarly to TRAF1(-/-) T cells, LSP1(-/-) T cells exhibit impaired ERK activation following stimulation through 4-1BB and consequently, are unable to down-modulate expression of the proapoptotic Bcl-2 family member Bim. Moreover, we demonstrate that the absence of LSP1 expression leads to defective expansion and survival of T cells in response to 4-1BB stimulation. Thus, we have identified LSP1 as a new mediator involved in 4-1BB signaling and T cell survival. Collectively, our work shows that TRAF1 and LSP1 cooperate downstream of 4-1BB to activate ERK signaling and down-modulate the levels of Bim leading to enhanced T cell survival.

Mitochondrial Morphological and Functional Reprogramming Following CD137 (4-1BB) Costimulation

“…Our results indicate a role for the AKT-mTOR route, whose function is upregulated by CD137 stimulation (38,39). Yet, the mechanistic connection of CD137 crosslinking to such downstream events needs to be linked to the proximal signaling events at the CD137-TRAF2-TRAF-1 complexes (30,40). Our results rule out a critical dependency on autocrine IL2 or IFNγ for CD137-induced mitochondrial invigoration, but other soluble mediators might be involved.…”

TRAF molecules in cell signaling and in human diseases

“…In response to BAFF stimulation, a signaling pathway of c-Raf-MEK-ERKdependent phosphorylation and down-regulation of the pro-apoptotic protein Bim also contributes to B cell survival [76]. In light of the evidence that TRAF1 mediates 4-1BB-induced ERK-dependent phosphorylation and down-regulation of Bim to promote T cell survival [77][78][79], it would be interesting to investigate the role of TRAF1 in BAFF-induced Bim down-regulation in B cells. Collectively, the above evidence indicates that TRAFs are critical regulators of signaling by the TNF-R superfamily.…”

Transgenic 4-1BBL-engineered vaccine stimulates potent Gag-specific therapeutic and long-term immunity via increased priming of CD44+CD62Lhigh IL-7R+ CTLs with up- and downregulation of anti- and pro-apoptosis genes

“…29 Recently, it has been shown that 41BB signaling enhances T-cell survival via the cooperation of tumor-necrosis factor (TNF) receptor-1 (TNFR1) and leukocyte-specific protein-1, leading to the activation of ERK and Bcl-2-interacting mediator of cell-death. 30 In this study, we demonstrated that 4-1BBL signaling up-and downregulated the expression of anti-apoptosis (Bcl2l10, Naip1, Nol3, Pak7 and Tnfrsf11b) and pro-apoptosis (Casp12, Trp63 and Trp73) genes, respectively, in CD8 1 CTLs with prolonged survival. It has also been reported that 4-1BBL can interact with Toll-like receptors (TLRs) to sustain TNF production.…”