CD137 (4-1BB) Signalosome: Complexity Is a Matter of TRAFs

Abstract

CD137 (4-1BB, Tnsfr9) is a member of the TNF-receptor (TNFR) superfamily without known intrinsic enzymatic activity in its cytoplasmic domain. Hence, akin to other members of the TNFR family, it relies on the TNFR-Associated-Factor (TRAF) family of adaptor proteins to build the CD137 signalosome for transducing signals into the cell. Thus, upon CD137 activation by binding of CD137L trimers or by crosslinking with agonist monoclonal antibodies, TRAF1, TRAF2, and TRAF3 are readily recruited to the cytoplasmic domain of CD137, likely as homo- and/or heterotrimers with different configurations, initiating the construction of the CD137 signalosome. The formation of TRAF2-RING dimers between TRAF2 molecules from contiguous trimers would help to establish a multimeric structure of TRAF-trimers that is probably essential for CD137 signaling. In addition, available studies have identified a large number of proteins that are recruited to CD137:TRAF complexes including ubiquitin ligases and proteases, kinases, and modulatory proteins. Working in a coordinated fashion, these CD137-signalosomes will ultimately promote CD137-mediated T cell proliferation and survival and will endow T cells with stronger effector functions. Current evidence allows to envision the molecular events that might take place in the early stages of CD137-signalosome formation, underscoring the key roles of TRAFs and of K63 and K48-ubiquitination of target proteins in the signaling process. Understanding the composition and fine regulation of CD137-signalosomes assembly and disassembly will be key to improve the therapeutic activities of chimeric antigen receptors (CARs) encompassing the CD137 cytoplasmic domain and a new generation of CD137 agonists for the treatment of cancer.

CD137 ligand feedback upregulates PD‐L1 expression on lung cancer via T cell production of IFN‐γ

“…Additionally, the CD137L expression on HCC‐827 cells significantly induced IFN‐γ production because this could be completely inhibited by treatment with anti‐CD137 mAb. It has been suggested that CD137 is sensitive to stimulation by CD137L, so even these low expression levels might be sufficient to trigger CD137 signaling upon interaction with CD137L. More interestingly, we found that anti‐CD137 mAb can also induce the expression of PD‐L1 in lung cancer cells and synergize with IFN‐γ.…”

Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations

“…1 As early as 1975, Lafferty and Cunningham 2 proposed that in addition to antigenic stimuli, full activation of antigen-specific T cells required secondary signals from antigen-presenting cells (APCs). 3,4 Costimulatory receptors of the Ig superfamily tend to activate phosphatidylinositol 3-kinase (PI3K) leading to protein kinase B (Akt) and downstream nuclear factor jB (NF-jB) activation, while TNFR superfamily members preferentially recruit and activate TNF receptorassociated factors (TRAFs) to potentiate NF-jB activation. 3 Later observations confirmed that antigenic stimulation without sufficient costimulation results in T cell anergy and T cell susceptibility to activation-induced cell death (AICD).…”

“…Confirmation of this classical two-signal hypothesis was achieved with the generation of antibodies that block costimulatory molecules, and the cloning of B7 family members CD80 and CD86, which are ligands for the prototypical T cell costimulatory receptor CD28. 3,4 Examples of costimulatory molecules expressed by T cells include CD28, ICOS, CD27, 4-1BB, OX40 and CD40L (see Table 1). 3 Broadly defined as cell surface molecules that can transduce signals into T cells to enhance TCRmediated signals, 1 most costimulatory receptors belong to the immunoglobulin (Ig) or tumor necrosis factor receptor (TNFR) superfamilies, and bind to ligands expressed by activated or licensed APCs.…”

“…11,29,30 4-1BB (CD137) 4-1BB (TNFRSF9, CD137) is an activation-induced T cell costimulatory molecule, first described in 1989. 4 Agonistic stimulation of 4-1BB upregulates expression of the anti-apoptotic proteins Bcl-x L and Bfl-1 and prevents AICD, 6 while 4-1BB activation increases IL-2 and IFN-c in CD8 + cells and IL-2 and IL-4 in CD4 + cells, the presence of two TRAF2 binding motifs being essential for downstream IL-2 production. 31 Upon binding to trimeric 4-1BBL (TNFSF9, CD137L) on APCs, 4-1BB recruits TNFR-associated factor family members (TRAF1, TRAF2 and TRAF3) to its cytosolic region, forming the 4-1BB signalosome and leading to downstream activation of NF-jB, MAPK and ERK.…”

“…3 Broadly defined as cell surface molecules that can transduce signals into T cells to enhance TCRmediated signals, 1 most costimulatory receptors belong to the immunoglobulin (Ig) or tumor necrosis factor receptor (TNFR) superfamilies, and bind to ligands expressed by activated or licensed APCs. 3,4 Costimulatory receptors of the Ig superfamily tend to activate phosphatidylinositol 3-kinase (PI3K) leading to protein kinase B (Akt) and downstream nuclear factor jB (NF-jB) activation, while TNFR superfamily members preferentially recruit and activate TNF receptorassociated factors (TRAFs) to potentiate NF-jB activation. 3,4 Examples of costimulatory molecules expressed by T cells include CD28, ICOS, CD27, 4-1BB, OX40 and CD40L (see Table 1).…”