NK RECEPTORS AND CD1 ROLES IN NK AND NK T CELL FUNCTION

Brown University, Providence RI

Investigators

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Abstract

DESCRIPTION: (Adapted from applicant's abstract) 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 IFN-gamma and/or lL-4 following stimulation. NK T cells have been implicated in a variety of immune responses, including the response to tumors and the regulation of autoimmune disease progression. The investigators hypothesize that CD1 mediated NK T cell responses may be regulated by the inhibitory and activating NK receptors expressed by NK T cells. It is proposed 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. The investigators believe that by testing the NK T cell hybridoma transfectants against a panel of CD1+ APC, insight may be gained into the class I specificity of NK receptors whose specificity is unknown. Experiments will be carried out with primary NK T cells to study how the NK receptors identified in the previous aims 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, they have made the surprising finding that a subset of NK cells have inhibitory receptors that interact with CD1, although CD1 is only very distantly related to the MHC class I molecules. The ability of some NK receptors to interact with CD1, has led them to hypothesize that an NK receptor could act as a co-receptor for the CD1 reactive NK T cell TCR. Therefore, they propose here to undertake several strategies to identify the CD1 binding NK receptor(s) and they will determine if these act as a co-receptors for the NK T cell TCR. The investigators believe that these novel studies will provide insight into the specificity and immunoregulatory role of NK receptors on both CD1 reactive NK T cells and NK cells, and they may provide strategies for the regulation of this important category of immune cell responses.