UCSF

Abstract

The activity of a Natural Killer (NK) cells is regulated by the collective balance of activating and inhibitory signals from surface receptors. The work described here focuses on the biology of human NK receptors, NKG2D & NKR-P1A.

NKG2D recognizes stress-inducible ligands present on virally infected cells, cancer cells, & cells that have experienced genotoxic damage. While NKG2D does not contain any recognizable signaling motifs, it was previously known to pair with a transmembrane adapter signaling protein, DAP10, to initiate signal transduction events. More recently, studies have revealed that alternative mRNA splicing of the mouse NKG2D gene generates receptors that associate with either the DAP10 or DAP12 transmembrane adapter signaling proteins. Here we report that NKG2D function is normal in human patients lacking functional DAP12, indicating that DAP10 is sufficient for human NKG2D signal transduction. Further, we show that human NKG2D is incapable of associating with DAP12 and provide evidence that structural differences in the transmembrane of mouse and human NKG2D account for the species-specific difference for this immune receptor.

Another C-type lectin whose function has remained largely enigmatic is human NKR-P1A (CD161), present on NK cells and subsets of T cells. In these studies, we demonstrate that lectin-like transcript-1 (LLT1) is a physiological ligand for NKR-P1A. LLT1-containing liposomes bind to NKR-P1A+ cells and binding is inhibited by anti-NKR-P1A mAb. Additionally, LLT1 activates NFAT-GFP reporter cells expressing a CD3ζ-NKR-P1A chimeric receptor; reciprocally, reporter cells with a CD3ζ -LLT1 chimeric receptor are stimulated by NKR-P1A. Moreover, LLT1 on target cells can inhibit NK cytotoxicity and cytokine production via interactions with NKR-P1A.

We further demonstrate that Lectin-like Transcript 1 is expressed on activated lymphocytes. We show that activated primary B cells and many B cell lines express LLT1, activated plasmacytoid dendritic cells and activated monocyte-derived dendritic cells express LLT1, and interestingly, activated T cells seem to express LLT1 as well. Lastly we explore the role of NKR-P1A on T cells and find that while engaging NKR-P1A with antibodies on CD8+ T cells can inhibit TNFα production, NKR-P1A does not seem to play any obvious role in CD4+ T cell cytokine production.