The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated

Killer-cell Ig-like receptors (KIR) are structurally and functionally diverse, and enable human NK cells to survey the expression of individual HLA class I molecules, often altered in infections and tumors. Multiple events of non-reciprocal recombination have contributed to the rapid diversification of KIR. We show that approximately 4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1. The KIR3DP1 gene is normally silent, but the recombinant allele carries a novel promoter sequence and, as a consequence, is transcribed in all tested individuals. Messenger RNA of KIR3DP1*004 is made up of six exons; of these, exons 1-5 are similar to, and spliced like, those encoding the leader peptide and Ig-domains of KIR3D. By contrast, exon 6 is homologous to no other human KIR sequence, but only to possible homologs in chimpanzees and rhesus macaques, and encodes a short hydrophilic tail. The putative KIR3DP1*004 product, like those of the related genes LAIR-2 and LILRA3/ILT6/LIR4, is predicted to be secreted to the extracellular medium rather than anchored to the cell membrane.     

NK cells can generate from precursors in the adult human liver

Hepatic NK cells constitute ≈ 40% of hepatic lymphocytes and are phenotypically and functionally distinct from blood NK cells. Whether hepatic NK cells derive from precursors in the BM or develop locally from hepatic progenitors is still unknown. Here, we identify all five known sequential stages of NK-cell development in the adult human liver and demonstrate that CD34(+) hepatic progenitors can generate functional NK cells. While early NK-cell precursors (NKPs) were similar in liver and blood, hepatic stage 3 NKPs displayed immunophenotypical differences, suggesting the onset of a liver-specific NK-cell development. Hepatic stage 3 NKPs were RORC(neg) and did not produce IL-17 or IL-22, excluding them from the lymphoid tissue-inducer (LTi) subset. In vitro culture of hepatic NKPs gave rise to functional NK cells exhibiting strong cytotoxicity against K562 targets. To determine whether hepatic NKPs are stably residing in the liver, we analyzed donor and recipient-derived cells in transplanted livers. Shortly after liver transplantation all donor NKPs in liver grafts were replaced by recipient-derived ones, indicating that hepatic NKPs are recruited from the bloodstream. Together, our results show that NKPs are continuously recruited from peripheral blood into the liver and can potentially differentiate into liver-specific NK cells.     

A role for plasmacytoid dendritic cells in the rapid IL-18-dependent activation of NK cells following HSV-1 infection

Natural killer (NK) cells play a crucial role in the initial response to viral infections but the mechanisms controlling their activation are unclear. We show a rapid and transient activation of NK cells that results in the production of IFN-gamma immediately following infection with herpes simplex virus type 1 (HSV-1). Activation of NK cells leading to synthesis of IFN-gamma was not mediated by a direct interaction with virus but required the presence of additional cell types and was largely dependent on the cytokine IL-18, but not IL-12. HSV-1-induced IFN-gamma expression by NK cells in vitro was impaired in spleen cultures depleted of CD11c(+) cells. Conversely, coculture of NK cells with virus-exposed conventional DC or plasmacytoid (p)DC restored the production of IFN-gamma, indicating that multiple DC subsets could mediate NK cell activation. While conventional DC populations stimulated NK cells independently of IL-18, they were less effective than pDC in promoting NK cell IFN-gamma expression. In contrast, the potent stimulation of NK cells by pDC was dependent on IL-18 as pDC from IL-18-deficient mice only activated a similar proportion of NK cells as conventional DC. These data identify IL-18 as a crucial factor for pDC-mediated NK cell regulation.     

B-1a cells are imprinted by the microenvironment in spleen and peritoneum

B-1a cells are found mainly in the peritoneal cavity of mice but are also present in the spleen. Gene expression profiling defined many genes differentially expressed in B-1a cells from these two sites. To see whether this gene expression pattern was imprinted by the particular microenvironment, peritoneal or spleen cells from recombinant L2 mice mainly consisting of B-1a cells were adoptively transferred into Rag1-/- mice. Re-isolated peritoneal and splenic B-1a cells were analyzed for expression of three indicator genes--vcam-1, adamdec1 and spi-c. The expression of these genes was up-regulated in splenic and down-regulated in peritoneal cells. This particular pattern was observed for peritoneal or splenic donor cells transferred either intraperitoneally or intravenously. Similar results were obtained when levels of surface IgM or frequencies of Mac-1+ B-1 cells were compared after transfer. This suggests that the environment induces the particular genetic program of B-1a cells and argues against an independent ontogeny.