Abstract
The inhibitory effect of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters DAP12 and FcεRI γ-chain (FcRγ) has been found in many immune functions. Herein, we have further explored the role of these adapters in C-type lectin receptors response. We identified that FcRγ, but not DAP12, could negatively regulate the Dectin-1 responses in dendritic cells (DCs). Loss of FcRγ or both DAP12 and FcRγ enhanced the maturation and cytokine production in DCs upon Dectin-1 activation compared to normal cells, whereas DCs lacking only DAP12 showed little changes. In addition, increments of T cell activation and T helper 17 polarization induced by FcRγ-deficient DCs were observed both in vitro and in vivo. Examining the Dectin-1 signaling, we revealed that the activations of several signaling molecules were augmented in FcRγ-deficient DCs stimulated with Dectin-1 ligands. Furthermore, we demonstrated that the association of phosphatases SHP-1 and PTEN with FcRγ may contribute to the negative regulation of FcRγ in Dectin-1 activation in DCs. These results extend the inhibitory effect of ITAM-containing adapters to Dectin-1 response in immune functions, even though Dectin-1 contains an ITAM-like intracellular domain. According to the role of Dectin-1 in responding to microbes and tumor cells, our finding may have applications in the development of vaccine and cancer therapy.
Highlights
Dendritic cells (DCs) monitor danger signals in surrounding environment, capture and process antigens, migrate to secondary lymphoid organs, and activate T cells to initiate immune responses [1]
We identified that both DAP12 and FcεRI γ-chain (FcRγ) are required for inhibition of toll-like receptors (TLRs) responses in dendritic cells (DCs) [22]
Because immunoreceptor tyrosine-based activation motif (ITAM) is not involved in TLR signaling, we examined the effect of DAP12 and FcRγ on Dectin-1, which contains a hemITAM, in this study
Summary
Dendritic cells (DCs) monitor danger signals in surrounding environment, capture and process antigens, migrate to secondary lymphoid organs, and activate T cells to initiate immune responses [1]. DCs are heterogenous but all subsets have intrinsic and cooperative immunoregulatory functions [2]. They can direct immune responses either toward to tolerance or inflammatory reactions, which include cellular and humoral immune responses [3, 4]. DCs are provided with diverse receptors that sense microbial components and trigger host responses to invading pathogens. These receptors, known as pattern recognition receptors (PRRs), include toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and RIG-like receptors
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