Fc receptor γ-chain activation via hOSCAR induces survival and maturation of dendritic cells and modulates Toll-like receptor responses

Abstract

IntroductionDendritic cells (DCs) are potent antigen-presenting cells that have a unique ability to prime naive T cells. 1 In addition, they secrete immune-modulating factors that play a key role in the initiation and regulation of both innate resistance and adaptive immunity. DCs undergo striking changes in function and morphology depending on their maturation state and localization. 1 Immature DCs, located in peripheral tissues, are considered immune sentinels and are able to capture and process antigens. 2 Upon activation and maturation induced by proinflammatory signals, such as pathogen-associated molecular patterns (PAMPs), 3 they migrate to the T-cell areas of secondary lymphoid organs, where they are able to present antigens to naive T cells. 4,5 The outcome of the immune response (either immune priming or tolerance) is directly linked to the maturation status of DCs,6 which is generally believed to be induced by endogenous factors such as proinflammatory cytokines (tumor necrosis factor [TNF] or interleukin-1␤ [IL-1␤]) 7,8 or by exogenous products such as PAMPs (eg, lipopolysaccharide [LPS], lipoteichoic acid [LTA], or viral-RNA mimics such as polyinosinicpolycytidylic acid [poly(I:C)]). 9 DC activity can be regulated by both activating and inhibiting immune receptors that transduce signals through immunoreceptor tyrosine-based activating motifs (ITAM; consensus: D/Ex 7 D/ Ex 2 Yx 2 L/Ix 7 Yx 2 L/I) 10,11 and through immunoreceptor tyrosinebased inhibitory motifs (ITIM; consensus: I/V/L/SxYx 2 L/V), 12,13 respectively. This growing family of receptors was first described in lymphocytes, [14][15][16] but in recent years an increasing number of receptors of the lectin and the immunoglobulin superfamilies (IgSFs) linked to ITAM/ITIM signaling expressed on myeloid cells and DCs has been described. 17,18 These data indicate that cells of the myeloid lineage have a large number and variety of receptors regulating their activity. These receptors signal through activating or inhibiting pathways that regulate the amplitude and the duration of the immune response triggered by pathogenic stimuli. [19][20][21] We recently described human osteoclast-associated receptor (hOSCAR), a novel immune receptor associated with the Fc receptor ␥-chain (FcR␥) and involved in endocytosis and antigen presentation through the major histocompatibility complex (MHC) class II pathway in monocyte-derived dendritic cells (monoDCs). 22 Its association with an ITAM-bearing chain confers to hOSCAR the capacity to activate myeloid cells as shown by its ability to trigger calcium flux and cytokine release. 22 As hOSCAR is expressed by both immature and LPS-matured mono-DCs, we proposed that hOSCAR may have a biologic role on human DCs that is probably different to the previously described activating receptors such as the Fc receptors (FcRs) and triggering receptor expressed on myeloid cells-2 (TREM-2), the expression of which is down-regulated after activation of DCs. In contrast to the human receptor, mouse OSCAR (mOSCAR) is only express...

CD85j (Leukocyte Ig-Like Receptor-1/Ig-Like Transcript 2) Inhibits Human Osteoclast-Associated Receptor-Mediated Activation of Human Dendritic Cells

“…Its association with the ITAM-bearing FcR␥ confers to hOSCAR the capacity to activate myeloid cells as shown by its ability to trigger calcium flux and cytokine release (36). We also showed that hOSCAR ligation induced phenotypic and functional maturation of DCs, elicited cytokine and chemokine secretion, and synergistically amplified the TLR-induced ability of DCs to prime naive T cell proliferation (37). Unlike hOSCAR, mouse (m)OSCAR is expressed only on osteoclasts (38), which, like certain DC subsets, derive from the myeloid lineage.…”

“…Thus, it is conceivable that hOSCAR acts to induce DC maturation in the presence of its ligand. hOSCAR-activated DCs improve their survival and up-regulate the production of immune modulators, such as chemokines and cytokines (37). CD85j abrogated these responses and, consequently, could be a component of a regulatory loop that is active in a physiologic context.…”

“…5 and Ref. 37). The concomitant cross-linking of CD85j and hOSCAR reconstituted DC apoptosis to levels similar to those of cells cultured in the absence of survival factors (Fig.…”

“…In the absence of survival factors such as GM-CSF and IL-4, immature DCs underwent apoptosis from which they were rescued by cross-linking of hOSCAR (37). The ability of CD85j to prevent the rescue of DC apoptosis mediated by hOSCAR was therefore investigated.…”

“…hOSCAR (36,37) provided the strongest activating signal for DCs and was therefore chosen for all of the experiments. We show that CD85j inhibits intracellular calcium mobilization and cytokine secretion triggered by ligation of hOSCAR.…”