Human NK Cell Regulation at the Interface of Innate and Acquired Immunity

• Applicant: Professor Dr. Roland Jacobs
• Subject Area: Immunology
• Term: from 2002 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5356986

NK cells represent important early effector cells in host´s innate immune defense as they exert their functions without prior sensitization. They participate in regulation of innate and adaptive immune response and hematopoiesis by producing various cytokines. In addition, NK cells lyse virally infected and malignant cells raising them to multifunctional members of the first line of defense. Unlike other lymphocytes they lack specific antigen receptors. They rather are able to bind cells using ubiquitous molecules. In addition, they communicate via a pattern of receptors specific for MHC-I molecules (KIRs, KLRs). In general, successful binding of the latter receptors delivers an inhibitory signal to NK cells sparing the bound target cell from lysis. In the other case, down-regulated or altered MHC-I expression as frequently observed in virus infection or malignancy prevents ligation of KIRs and MHC-I paralyzing inhibition thus inducing lysis of the target cell. Data from our own laboratory and other groups indicate that there are additional mechanisms regulating NK cells. For instance, there is restriction of cytotoxic capacity and preference to produce cytokines in particular NK cell subsets. The mechanisms by which these different functions are regulated in particular NK cell populations is completely unknown. Furthermore, our own data suggest a direct regulation of NK cell-mediated cytotoxicity by autologous white blood cells in HIV-infected patients. Again, the underlying mechanisms are yet to be elucidated. In the last decade the view of NK cells has been changed substantially. Initially, NK cells have been considered a homogeneous cell population exerting all the different functions. Nowadays, it is generally accepted that NK cells comprise subpopulations of distinct phenotypes with different functional features. Aim of this study is a detailed phenotypical and functional characterization of the different NK cell subsets. We expect from these studies clarification of regulative mechanisms that are provided by and act on NK cells, respectively. The understanding of the exact functions of the particular NK cell subpopulations and exploration of prerequisites specifically triggering the various NK cell subsets may open up new therapeutical approaches.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1110: Innate Immunity
• Participating Person: Professor Dr. Reinhold Ernst Schmidt (†)