CD137 ligand reverse signaling has multiple functions in human dendritic cells during an adaptive immune response

Abstract

T cell activation via dendritic cells (DC) is an important step in the adaptive immune response, which requires DC maturation, migration to lymph nodes and presentation of antigen to T cells. CD137 receptor expressed on activated T cells is a potent costimulatory molecule. Here, we investigated the functions of CD137 ligand (CD137L) in human monocyte-derived DC during an immune response. Cross-linking of CD137L on DC leads to cell maturation in an autocrine fashion, mostly via release of TNF-a. Reverse signaling of CD137L also mediates migration of DC via up-regulation of the CCR7 chemokine receptor, demonstrated by an in vivo MIP-3b-dependent SCID mouse migration model. Finally, CD137L-activated DC induce differentiation of human T cells into potent Th1 effectors. Cocultivation of autologous T cells and CD137L-activated DC in an antigen-specific reaction leads to T cell proliferation and the release of IL-12p70 and IFN-c. These findings deliver new insights into the multiple effects of reverse signaling of CD137L in human DC during the initiation of an adaptive immune response, including the key features of DC maturation, migration and, ultimately, antigen-specific T cell differentiation.

CD137 ligand‐mediated reverse signals increase cell viability and cytokine expression in murine myeloid cells: Involvement of mTOR/p70S6 kinase and Akt

“…On the other hand, others showed that CD137L ligation enhances proliferation of hematopietic progenitor cells and its differentiation to monocytes, macrophages [34,35]. Reverse signals of CD137L enhances DC maturation and subsequent antigen-specific T-cell differentiation [36]. These together with previous studies using transgenic mice, knockout mice or mice injected with anti-CD137L Ab [19,37,38] clearly show potential in vivo effects of CD137L on innate immunity, although there are some discrepancies in the effects of CD137L.…”

CD137 Promotes Proliferation and Survival of Human B Cells

“…2). In this scenario, the interaction of CD137L + B cells with CD137 + B cells might bidirectionally costimulate B cells and mediate cell functional changes, because CD137L can also transduce signals in certain cell types (37)(38)(39).…”

Reverse Signaling through the Co-Stimulatory Ligand, CD137L, as a Critical Mediator of Sterile Inflammation

“…In particular, prominent phenotypic changes in monocytes/macrophages follow CD137L stimulation, such as cell proliferation, production of pro-inflammatory cytokines and chemokines, and up-regulation of cell adhesion molecules, thus enhancing the inflammatory response in an autocrine or paracrine fashion (reviewed in Shao and Schwarz, 2011). CD137L signaling mediates similar activities in dendritic cells that are observable in monocytes/ macrophages: cross-linking CD137L enhances the expression of co-stimulatory ligands and MHC molecules and cytokine release (Lippert et al, 2008). Deficient CD137L signaling induces myelopoiesis (Lee et al, 2008).…”