Regulation of NK cell function

ongoing

The human immune system has evolved sophisticated mechanisms to recognize and eliminate infected, stressed or cancer cells. Presentation of antigens by HLA-I enables the identification of diseased cells by antigen-specific T cells, while changes in HLA-I expression levels are sensed by NK cells. Many human NK cell receptors bind HLA-I; but whether and how NK cells might interact with HLA-II remained unknown. We recently discovered that a subset of commonly expressed HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44, implicating HLA-II in the regulation of NK cells. Remarkably, the strength of NKp44-binding to HLA-DP was dependent on both the HLA-DP allotype and the HLA-DP-presented peptide. The ability of NK cell receptors to bind HLA-II molecules represents a paradigm shift from previous models describing NK cell function largely in the context of HLA-I, and suggests a novel regulatory framework in which NK cells interact directly with HLA-II-expressing cells, including APCs and activated stroma cells. HLA-DP allotypes have been associated with the incidence and outcome of several infectious and inflammatory diseases, and the newly identified interactions between HLA-DP and NKp44 now provide a molecular mechanism implicating NK cells in the pathogenesis of these diseases. As NKp44 and HLA-DP are not expressed in mice, but have evolved recently in primates and humans, studies investigating the underlying mechanisms have to be performed in humans. The applicant proposes an innovative and integrated research program, combining functional immunological and virological approaches with recently developed human organoid systems and proteomics technologies to investigate the impact of interactions between NKp44 and HLA-DP for human diseases, with the ultimate goal to harness NK cells for immunotherapeutic interventions against infections and inflammatory diseases.