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Plasmacytoid dendritic cell dichotomy: identification of IFN-? producing cells as a phenotypically and functionally distinct subset.

ABSTRACT: Plasmacytoid dendritic cells (pDC) produce large amounts of type I IFN in response to invading pathogens, but can also suppress immune responses and promote tolerance. In this study, we show that in mice, these functions are attributable to two distinct pDC subsets, one of which gives rise to the other. CD9(pos)Siglec-H(low) pDC secrete IFN-? when stimulated with TLR agonists, induce CTLs, and promote protective antitumor immunity. By contrast, CD9(neg)Siglec-H(high) pDC secrete negligible amounts of IFN-?, induce Foxp3(+) CD4(+) T cells, and fail to promote antitumor immunity. Although newly formed pDC in the bone marrow are CD9(pos) and are capable of producing IFN-?, after these cells traffic to peripheral tissues, they lose CD9 expression and the ability to produce IFN-?. We propose that newly generated pDC mobilized from the bone marrow, rather than tissue-resident pDC, are the major source of IFN-? in infected hosts.

SUBMITTER: Bjorck P

PROVIDER: S-EPMC3138736 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Plasmacytoid dendritic cell dichotomy: identification of IFN-α producing cells as a phenotypically and functionally distinct subset.

Björck Pia P Leong H Xianne HX Engleman Edgar G EG

Journal of immunology (Baltimore, Md. : 1950) 20101220 3

Plasmacytoid dendritic cells (pDC) produce large amounts of type I IFN in response to invading pathogens, but can also suppress immune responses and promote tolerance. In this study, we show that in mice, these functions are attributable to two distinct pDC subsets, one of which gives rise to the other. CD9(pos)Siglec-H(low) pDC secrete IFN-α when stimulated with TLR agonists, induce CTLs, and promote protective antitumor immunity. By contrast, CD9(neg)Siglec-H(high) pDC secrete negligible amoun ...[more]

PMID: 21172865

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Project description:BackgroundThe murine discs large homolog 2 (DLG2; post synaptic density 93 (PSD-93); Chapsyn-110) is a member of the membrane-associated guanylate kinase (MAGUK) protein family involved in receptor assembly and associated with signaling enzymes on cell membranes. In neurons, DLG2 protein isoforms derived from alternatively spliced transcripts have been described to bind to NMDA (N-methyl-aspartate) receptors and K channels and to mediate clustering of these channels in the postsynaptic membrane. In myeloid cells of the immune system, such as dendritic cells (DCs), a lack of data exists on the expression or function of DLG2. In cDNA microarray transcriptome analyses, we found Dlg2 highly expressed in a subpopulation of plasmacytoid DCs (pDCs) stimulated to produce type I interferons (IFNs) such as IFNβ.ResultsUsing RACE- and RT-PCR as well as immunoprecipitation followed by Western blotting we characterised the differential expression of the Dlg2 splice variants in IFNβ-producing pDCs. Besides Dlg2ɣ this cell population expressed a novel short Dlg2η transcript we termed Dlg2η3. Our expression data were integrated into information from genome databases to obtain a novel and comprehensive overview of the mouse Dlg2 gene architecture. To elucidate the intracellular localisation pattern of protein isoforms, ectopical expression analysis of fluorescently tagged DLG2 splice variants was performed. Here we found an enrichment of the larger isoform DLG2α1 at the plasma membrane while the newly identified shorter (DLG2η) isoform as well as DLG2ɣ were equally distributed throughout the cytoplasm. Additionally, DLG2η was also found in the nucleus. Analysis of Dlg2-knockout mice previously generated by deleting exon 9 surprisingly revealed that the protein for the novel DLG2η isoform was still expressed in the brain and in bone marrow-derived pDCs from mice carrying the homozygous deletion (Dlg2 ΔE9/ΔE9 ).ConclusionWe describe a novel splice variant of the mouse Dlg2 gene termed Dlg2η and define the differential expression pattern of DLG2 isoforms in IFNβ-producing pDCs. The presence of DLG2η protein in the CNS of Dlg2 ΔE9/ΔE9 mice might influence the phenotype of these mice and has to be taken into account in the interpretation of results regarding the functional role of DLG2 in neuronal postsynaptic membranes.

Dataset Information

Plasmacytoid dendritic cell dichotomy: identification of IFN-? producing cells as a phenotypically and functionally distinct subset.

Publications

Plasmacytoid dendritic cell dichotomy: identification of IFN-α producing cells as a phenotypically and functionally distinct subset.

Similar Datasets

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