DAP12 Signaling Regulates Plasmacytoid Dendritic Cell Homeostasis and Down-Modulates Their Function during Viral Infection

Abstract

DAP12 is an ITAM-containing adaptor molecule conveying activating properties to surface receptors on many cell types. We show here that DAP12 paradoxically down-modulates plasmacytoid dendritic cell (pDC) cytokine production in vivo during murine CMV (MCMV) infection. Higher levels of IFN-αβ and IL-12 were detected upon MCMV infection or CpG treatment in DAP12-deficient (DAP12°) mice as compared with wild-type (WT) mice. This resulted from altered homeostasis and enhanced responsiveness of pDCs in DAP12° animals. Increased numbers of pDCs were observed in the periphery of both naive and MCMV-infected DAP12° mice. A higher proportion of pDCs was activated in infected DAP12° mice, as demonstrated by intracellular staining using an optimized protocol for simultaneous detection of IFN-α and IFN-β. The homeostasis of WT and DAP12° pDCs did not differ in mixed bone marrow chimeric mice. In addition, a similar efficiency of pDC differentiation was observed in vitro in Fms-like tyrosine kinase receptor 3 ligand cultures of WT and DAP12° bone marrow cells. This suggests that DAP12 signaling effects on pDC homeostasis are indirect. In contrast, in response to CpG, DAP12-mediated effects on both IL-12 and IFN-αβ production were intrinsic to the pDCs. However, in response to MCMV, only IL-12 but not IFN-αβ production was affected by pDC-intrinsic DAP12 signaling. Thus, DAP12 signaling in pDCs can mediate different regulatory effects on their functions, depending on the mechanisms of pDC activation. The potential implications of the regulation of pDC functions by DAP12 for promoting health over disease are discussed.

Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection

“…This notion is supported by the observations made in models of MCMV infection to which host defense relies largely on NK functions and thus lack of DAP12 leads to impaired NK activities and increased susceptibility (7)(8)(9). In this regard, the relationship between recently identified enhanced cytokine responses in DAP12-deficient plasmacytoid dendritic cells and decreased innate host resistance to MCMV infection in DAP12-deficient mice has remained unclear (21). However, in the situation where innate APC are critically required for the initiation and activation of T cell-mediated immunity, the outcome of DAP12 signaling within APC is determined by the nature of Ag or pathogen and its engagement with DAP12-associating molecules that are uniquely expressed on these cells.…”

Control of Pathogenic CD4 T Cells and Lethal Immunopathology by Signaling Immunoadaptor DAP12 during Influenza Infection

“…Thus, the role of DAP12 pathway may be proimmune when the host is exposed in vivo to inert Ags (39) or extracellular infectious agents or isolated pattern recognition receptor ligands (31,37,58). However, when the host is exposed to the intact intracellular infectious agents such as murine cytomegalovirus (35), Listeria monocytogene (34), Mycobacterium bovis (36), or influenza A virus (current study), DAP12 plays a critical immune suppressive role. As many innate immune receptors associate with and signal through DAP12 and the ligands for many of these receptors still remain unknown, identifying the potential ligands will help develop the effective immunotherapeutic strategies for fine-tuning host antimicrobial responses.…”

“…These data suggest that DAP12 pathway controls CD4 T cell responses via regulating the production of T cell-activating cytokines and Ag presentation by APC. Previous studies have shown that lack of DAP12 in APC led to the increased TLR signaling via enhanced Syk-ERK and PI3K activation (32)(33)(34)(35).…”

“…A number of innate immune receptors including the triggering receptor expressed on myeloid cells, MDL-1 and NKG2D, are associated with and signal though DAP12 (24)(25)(26)(27)(28)(29). Although initially identified to be a proinflammatory or immune-activating molecule, recent emerging evidence suggests a dual role of DAP12 signaling pathway, depending on the target immune cell type, the nature of Ags or infectious agents or the variation in different animal models (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). However, the precise role of DAP12 pathway in the regulation of immunopathogenic T cell subsets and immunopathology in acute influenza infection remains unclear.…”

PDC-TREM, a plasmacytoid dendritic cell-specific receptor, is responsible for augmented production of type I interferon

“…However, recent findings have also demonstrated that DAP12 mediates negative signals under some conditions (24,(36)(37)(38)(39). The mechanisms for the seemingly contradictory positive and negative signaling effects mediated by DAP12 are at present unknown.…”