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FcγRIIB prevents inflammatory type I IFN production from plasmacytoid dendritic cells during a viral memory response.

ABSTRACT: The type I IFN (IFN-α) response is crucial for viral clearance during primary viral infections. Plasmacytoid dendritic cells (pDCs) are important early responders during systemic viral infections and, in some cases, are the sole producers of IFN-α. However, their role in IFN-α production during memory responses is unclear. We found that IFN-α production is absent during a murine viral memory response, despite colocalization of virus and pDCs to the splenic marginal zone. The absence of IFN was dependent on circulating Ab and was reversed by the transgenic expression of the activating human FcγRIIA receptor on pDCs. Furthermore, FcγRIIB was required for Sendai virus immune complex uptake by splenic pDCs in vitro, and internalization via FcγRIIb prevented cargo from accessing TLR signaling endosomes. Thus, pDCs bind viral immune complexes via FcγRIIB and prevent IFN-α production in vivo during viral memory responses. This Ab-dependent IFN-α regulation may be an important mechanism by which the potentially deleterious effects of IFN-α are prevented during a secondary infection.

SUBMITTER: Flores M

PROVIDER: S-EPMC4820833 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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FcγRIIB prevents inflammatory type I IFN production from plasmacytoid dendritic cells during a viral memory response.

Flores Marcella M Chew Claude C Tyan Kevin K Huang Wu Qing WQ Salem Aliasger A Clynes Raphael R

Journal of immunology (Baltimore, Md. : 1950) 20150327 9

The type I IFN (IFN-α) response is crucial for viral clearance during primary viral infections. Plasmacytoid dendritic cells (pDCs) are important early responders during systemic viral infections and, in some cases, are the sole producers of IFN-α. However, their role in IFN-α production during memory responses is unclear. We found that IFN-α production is absent during a murine viral memory response, despite colocalization of virus and pDCs to the splenic marginal zone. The absence of IFN was d ...[more]

PMID: 25821224

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Project description:Recent studies have reported that the crosslinking of regulatory receptors (RRs), such as blood dendritic cell antigen 2 (BDCA-2) (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses the production of type I interferons (IFN-I, ?/?/?) and other cytokines in response to toll-like receptor 7 and 9 (TLR7/9) ligands. The exact mechanism of how this B cell receptor (BCR)-like signaling blocks TLR7/9-mediated IFN-I production is unknown. Here, we stimulated BCR-like signaling by ligation of RRs with BDCA-2 and ILT7 mAbs, hepatitis C virus particles, or BST2 expressing cells. We compared BCR-like signaling in proliferating pDC cell line GEN2.2 and in primary pDCs from healthy donors, and addressed the question of whether pharmacological targeting of BCR-like signaling can antagonize RR-induced pDC inhibition. To this end, we tested the TLR9-mediated production of IFN-I and proinflammatory cytokines in pDCs exposed to a panel of inhibitors of signaling molecules involved in BCR-like, MAPK, NF-?B, and calcium signaling pathways. We found that MEK1/2 inhibitors, PD0325901 and U0126 potentiated TLR9-mediated production of IFN-I in GEN2.2 cells. More importantly, MEK1/2 inhibitors significantly increased the TLR9-mediated IFN-I production blocked in both GEN2.2 cells and primary pDCs upon stimulation of BCR-like or phorbol 12-myristate 13-acetate-induced protein kinase C (PKC) signaling. Triggering of BCR-like and PKC signaling in pDCs resulted in an upregulation of the expression and phoshorylation of c-FOS, a downstream gene product of the MEK1/2-ERK pathway. We found that the total level of c-FOS was higher in proliferating GEN2.2 cells than in the resting primary pDCs. The PD0325901-facilitated restoration of the TLR9-mediated IFN-I production correlated with the abrogation of MEK1/2-ERK-c-FOS signaling. These results indicate that the MEK1/2-ERK pathway inhibits TLR9-mediated type I IFN production in pDCs and that pharmacological targeting of MEK1/2-ERK signaling could be a strategy to overcome immunotolerance of pDCs and re-establish their immunogenic activity.

Dataset Information

FcγRIIB prevents inflammatory type I IFN production from plasmacytoid dendritic cells during a viral memory response.

Publications

FcγRIIB prevents inflammatory type I IFN production from plasmacytoid dendritic cells during a viral memory response.

Similar Datasets

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