Molecular Basis of Cancer Cell Recognition and Killing by Human Natural Killer Cells

Natural Killer (NK) cells are a population of lymphocytes vital for the innate immune response. These cells protect the host during the early phase of infection before the adaptive immune response is effective. NK cells are direct effectors via cytoxicity towards neoplastic and infected cells. Additionally, they modulate the immune response by the production of cytokines, most notably interferon y and tumor necrosis factor a. Furthermore, NK cell receptors do not undergo rearrangement. Repetoires of activating and inhibitory receptors regulate the function of NK cells via a balance of signaling. NK cell receptors can broadly be divided by their ligand specificity as well. Most of the known receptors recognize MHC class I molecules and transduce inhibitory signals. This is the basis for the missing self hypothesis espoused by Karre and colleagues. The LY49 molecules server this function in the mouse and are related to the C-type lectins. In primates, a family of killer inhibitory receptors (KIR) appear to play the same role and are in the immunoglobulin (Ig) superfamily of receptors. Whether humans expressed the Ly49 receptors was a fundamental question in NK cell biology. In my attempt to address this issue, I isolated two receptors related to the C-type lectin receptors and localized to the human NK gene complex on chromosome 12 in a region syntenic to where the murine Ly49 genes reside. Functional characterization of these receptors will facilitate our understanding of NK cell biology. Additional activating receptors include the members of the CD2 subset of the immunoglobulin superfamily molecules expressed on NK cells and other leukocytes, including murine 2B4. 2B4 is the high affinity ligand for CD48. Engagement of 2B4 on NK cell surfaces with specific antibodies or CD 48 can trigger cell mediated cytotoxicity, IFN-y secretion, phosphoinositol turnover and NK cell invasiveness. This work describes the isolation and characterization of the human homologue of the 2B4 receptor. The putative peptide has a type I structure with one transmembrane domain. The extracellular region is comprised of two immunoglobulin like domains with six putative N-linked glycosylation sites. The cytoplasmic domain of 2B4 contains unique tyrosine motifs (TxYxxV/I) that associate with src homology 2 domain containing protein (SH2DIA) or signaling lymphocyte activation molecule (SLAM)-associate protein (SAP), whose mutation is the underlying genetic defect in the X-linked lymphoproliferative disease (XLPD). Impaired signaling via 2B4 and SLAM is implicated in the immunopathogenesis of XLPD. CS1 is a novel member of the CD2 subset that contains two of the unique tyrosine motifs present in 2B4 and SLAM. Signaling through 2B4, CS1 and other members of the CD2 subset may play a major role in the regulation of NK cells and other leukocyte functions.