NK Receptors and CD1 Roles in NK and NK T Cell Function

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DESCRIPTION: (Adapted from applicant's abstract) Murine CD1 molecules have the ability to present glycolipids to NK T cell. NK T cells are a lymphocyte subset that is characterized by the expression of an invariant TCR, autoreactivity to CD1 molecules, and the ability to rapidly produce large amounts of IFNy and/or IL-4 following stimulation. NK T cells have been implicated in a variety of immune responses, including the response to tumors, infectious agents and the regulation of autoimmune disease progression. We hypothesize that CD1 mediated NK T cell responses may be regulated by the inhibitory and activating NK receptors expressed by NK T cells. We propose to characterize the pattern of expression of inhibiting and activating NK receptors on mouse NK T cells and NK T cell hybridomas. In addition, a series of NK receptors will be tested for their ability to regulate the NK T cell activation induced by CD1 molecules, by transfecting them into NK T cell hybridomas. The specificity of the hybridomas is well characterized, and the strength of the stimulating antigen signal can be regulated by manipulating the amount of CD1 expressed on the APC, the amount of lipoglycan antigen used. Experiments also will be carried out with primary NK T cells to study how these NK receptors act in the context of immune responses in vivo and in vitro. While NK receptors are known to react with MHC encoded class I molecules, we have made the surprising finding that a subset of NK cells are inhibited by interaction with CD1, although CD1 is only very distantly related to the MHC class I molecules. Therefore, several strategies will be undertaken to identify the CD1 binding NK receptor(s), and we will determine if these act as co-receptors for the NKT cell .The dual role of CD1 molecule as an activating molecule through the TCR on NK T cells and as an inhibitory molecule through an inhibitory receptor on NK cells will be studied in the context of the murine cytomegalovirus infection of mice. This virus replicates in murine liver, an organ particularly rich in NK cell and NK T cells and with high amount of CD1 molecules on hepatocytes. These novel studies will provide insights into the: specificity and immunoregulatory role of NK receptors on both CD1 reactive NK T cells and NK cells, and provide strategies for the regulation of this important category of immune cell responses.