Select Clr-g Expression on Activated Dendritic Cells Facilitates Cognate Interaction with a Minor Subset of Splenic NK Cells Expressing the Inhibitory Nkrp1g Receptor

Abstract

Natural killer gene complex–encoded immunomodulatory C-type lectin-like receptors include members of the NKRP1 and C-type lectin-like 2 (CLEC2) gene families, which constitute genetically linked receptor-ligand pairs and are thought to allow for NK cell–mediated immunosurveillance of stressed or infected tissues. The mouse C-type lectin-like receptor Nkrp1g was previously shown to form several receptor-ligand pairs with the CLEC2 proteins Clr-d, Clr-f, and Clr-g, respectively. However, the physiological expression of Nkrp1g and its CLEC2 ligands as well as their functional relevance remained poorly understood. Recently, we demonstrated a gut-restricted expression of Clr-f on intestinal epithelial cells that is spatially matched by Nkrp1g on subsets of intraepithelial lymphocytes. In this study, we investigated expression and ligand interaction of Nkrp1g in the splenic compartment, and found an exclusive expression on a small subset of NK cells that upregulates Nkrp1g after cytokine exposure. Whereas transcripts of Clr-d and Clr-f are virtually absent from the spleen, Clr-g transcripts were abundantly detected throughout different leukocyte populations and hematopoietic cell lines. However, a newly generated anti–Clr-g mAb detected only residual Clr-g surface expression on splenic monocytes, whereas many hematopoietic cell lines brightly display Clr-g. Clr-g surface expression was strongly upregulated on splenic CD8α+ conventional dendritic cells (DCs) and plasmacytoid DCs upon TLR-mediated activation and detectable by Nkrp1g, which dampens NK cell effector functions upon Clr-g engagement. Hence, different to the intestinal tract, in the spleen, Nkrp1g is selectively expressed by a subset of NK cells, thereby potentially allowing for an inhibitory engagement with Clr-g-expressing activated DCs during immune responses.