CD137-Ligand induced apoptosis in peripheral blood mononuclear cells (PBMCs)

Abstract

CD137 and CD137 ligand (CD137) are well established immuno-modulators belonging to the TNFR and TNF superfamilies respectively. Signaling through CD137 on T cells provides potent co-stimulatory signals for T cell activation, cytokine production and functional maturation. CD137L expressed on antigen presenting cells (APCs) likewise signals for activation and differentiation of APCs, thereby leading to an amplification of the immune response.

However surprisingly, CD137L agonists have also been reported to inhibit cell proliferation and to induce cell death in PBMCs. Using recombinant CD137-Fc, we set out to clarify this paradox by investigating the underlying mechanism leading to cell death in PBMCs. Our studies have shown that CD137 selectively induces apoptosis in the T-cell sub-population of PBMCs. Although there is a CD137-mediated upregulation of death receptors, apoptosis is not promoted by the extrinsic pathway. We discovered that CD137-induced apoptosis cannot be rescued by pan-caspase inhibitors, but is instead critically dependent on reactive oxygen species (ROS) production. We identified that the key ROS involved in apoptosis is H2O2 and that H2O2 production is NADPH-oxidase dependent. Further investigation shows that T cell apoptosis is dependent on monocytes and correlates with monocyte: T cell ratio. This observation is reminiscent of monocyte dependent cell death (MDCD) and just as MDCD, CD137-induced, monocyte-mediated T cell apoptosis is cell-cell contact-dependent. Taking into consideration that T cell death is monocyte dependent, we further clarified that ROS critical to CD137-induced T cell death is not produced by monocytes but is directly induced in T cells.

Since cell death requires the presence of CD137-activated monocytes, we propose a novel physiological role for CD137 in mediating MDCD, potentially in the context of the limitation and termination of T cell and immune responses.