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DAP12 promotes IRAK-M expression and IL-10 production by liver myeloid dendritic cells and restrains their T cell allostimulatory ability
Journal article   Peer reviewed

DAP12 promotes IRAK-M expression and IL-10 production by liver myeloid dendritic cells and restrains their T cell allostimulatory ability

Tina L Sumpter, Vignesh Packiam, Heth R Turnquist, Antonino Castellaneta, Osamu Yoshida and Angus W Thomson
The Journal of immunology (1950), Vol.186(4), pp.1970-1980
02/15/2011
DOI: 10.4049/jimmunol.1000527
PMCID: PMC3805281
PMID: 21257958

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Abstract

Freshly isolated hepatic dendritic cells (DC) are comparatively immature, relatively resistant to maturation, and can downmodulate effector T cell responses. Molecular mechanisms that underlie these properties are ill defined. DNAX-activating protein of 12 kDa (DAP12) is an ITAM-bearing transmembrane adaptor protein that integrates signals through several receptors, including triggering receptor expressed on myeloid cells-1, -2, and CD200R. Notably, DC propagated from DAP12-deficient mice exhibit enhanced maturation in response to TLR ligation. Given the constitutive exposure of liver DC to endotoxin draining from the gut, we hypothesized that DAP12 might regulate liver DC maturation. We show that DAP12 is expressed by freshly isolated liver, spleen, kidney, and lung myeloid DC. Moreover, inhibition of DAP12 expression by liver DC using small interfering RNA promotes their phenotypic and functional maturation, resulting in enhanced TNF-α, IL-6, and IL-12p70 production, reduced secretion of IL-10, and enhanced CD4(+) and CD8(+) T cell proliferation. Furthermore, DAP12 silencing correlates with decreased STAT3 phosphorylation in mature liver DC and with diminished expression of the IL-1R-associated kinase-M, a negative regulator of TLR signaling. These findings highlight a regulatory role for DAP12 in hepatic DC maturation, and suggest a mechanism whereby this function may be induced/maintained.
 Adaptor Proteins, Signal Transducing - biosynthesis Adaptor Proteins, Signal Transducing - deficiency Adaptor Proteins, Signal Transducing - physiology Animals Cell Differentiation - genetics Cell Differentiation - immunology Cells, Cultured CHO Cells Coculture Techniques Cricetinae Cricetulus Dendritic Cells - cytology Dendritic Cells - immunology Dendritic Cells - metabolism Growth Inhibitors - biosynthesis Growth Inhibitors - deficiency Growth Inhibitors - physiology Immune Tolerance - genetics Interleukin-1 Receptor-Associated Kinases - antagonists & inhibitors Interleukin-1 Receptor-Associated Kinases - biosynthesis Interleukin-1 Receptor-Associated Kinases - genetics Interleukin-10 - antagonists & inhibitors Interleukin-10 - biosynthesis Interleukin-10 - physiology Liver - cytology Liver - immunology Liver - metabolism Lymphocyte Activation - genetics Lymphocyte Activation - immunology Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Myeloid Cells - cytology Myeloid Cells - immunology Myeloid Cells - metabolism T-Lymphocytes - cytology T-Lymphocytes - immunology T-Lymphocytes - metabolism

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