Molecular Aspects of Human CD1d Functions

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DESCRIPTION (provided by applicant): CD 1 molecules are cell surface glycoproteins homologous to MHC class I molecules that present autologous or antigenic lipids to specific T cells. In humans there are five CD1 genes and one of them, encoding CD1d molecules, is also present in mice. CD1d molecules are specifically recognized by a subset of T lymphocytes called NKT cells that play an important role in resistance to infection by producing large quantities of gamma-interferon or interleukin-4 when stimulated. The processing mechanisms responsible for mediating lipid association with CD 1d molecules are unknown. This proposal seeks to understand the mechanisms governing the association of lipids with assembling human CD 1d glycoproteins in the endoplasmic reticulum as well as during their passage through the endocytic pathway. The spectrum of lipids bound in each of these compartments will be identified as well as co-factors mediating the acquisition of these lipids. A subset of CD 1d molecules binds to assembling MHC class II glycoproteins in the endoplasmic reticulum and this interaction is maintained on the cell surface. Three potential effects of this association will be examined: alteration of the repertoire of peptides bound to MHC class II molecules; alteration of the repertoire of lipids bound to CD 1d molecules; and enhanced recognition of cell surface CD 1d-lipid complexes by CD4-positive, CD 1d-reactive T cells. Possible effects of a variety of stimuli, including stress responses and viral infection, on the recognition of CD 1d-expressing cells by CD 1d-restricted T lymphocytes and on the repertoire of CD 1d-associated lipids will also be examined.