The CD1 family of cell surface glycoproteins have recently been proposed to be a third lineage of antigen presenting molecules that have diverged markedly from the MHC class I and II families in their structure, function and pattern of expression. Remarkably, the antigens currently known to be presented to human CD1 restricted T cells are not peptides, but are unique lipid and glycolipid molecules found in bacterial cell walls. The CD1 system thus mediates recognition of an important set of nonpeptide antigens by T cells, and as such is likely to perform an important role in innate or acquired immunity to infectious pathogens. In this application, the antigen presenting function of CD1 will be demonstrated directly by using radiolabelled microbial glycolipid antigens as probes for antigen binding to CD1 proteins. A powerful new mass spectrometry technique (electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry) will be used to determine the structure of processed foreign glycolipid antigens bound to CD1. Since previous studies implicate an endosomal pathway for antigen processing in CD1 restricted responses, a variety of subcellular imaging and fractionation methods will be used to establish the particular endosomal compartments to which CD1 molecules localize, and the mechanisms that control the sorting of CD1 proteins to these sites will be determined. CD1 restricted T-cell lines specific for bacterial lipid and glycolipid antigens will be used to assess the functional importance of endosomal localization of CD1 proteins for presentation of exogenously or endogenously acquired antigens. These studies will help to establish a new paradigm for cellular immune recognition that expands our overall appreciation of how T cells see foreign antigens, and should have broad potential implications for the host response to foreign and self antigens in health and disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Special Emphasis Panel (ZRG2-ALY (01))
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Brigham and Women's Hospital
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