CD4+ T cells recognize exogenously derived peptide antigens. The antigens are taken up by APCs and loaded onto newly synthesized MHC class II molecules that intersect with an endosomal-lysosomal compartment where the antigens are proteolyzed. In contrast, polypeptides synthesized by cells are broken down to 8-10 residue peptides in the cytosol, transported into the ER, loaded onto class I MHC molecules and expressed on the cell surface for recognition by CD8+ T cells. We reasoned that alpha beta T cells lacking CD4 and CD8 coreceptors might recognize foreign antigens using antigen presenting molecules other than the classical MHC class I and II complexes. Here we characterize the antigen presenting pathway mediated by nonMHC encoded CD1 molecules. CD1 proteins consist of single heavy chains associated with beta2m thus resembling class I complexes. However, CD1 molecules present exogenously derived mycobacterial antigens via a chloroquine sensitive pathway. Surprisingly, the antigens presented are complex lipids displaying chromatographic characteristics typical of mycolic acids, a major component of the mycobacterial cell wall. Here we propose to purify and determine the fine structure of the bacterial lipids recognized by these alpha beta T cells. We examine critical steps in the assembly of CD1 proteins, including their interactions with the molecular chaperone calnexin, and with the invariant chain (Ii) that normally assembles with class II molecules. We test the hypothesis that Ii directs trafficking of newly synthesized CD1 molecules to intersect with endocytosed exogenously derived nonprotein antigens. We will determine if Ii plays an important role in antigen presentation by CD1 molecules by comparing recognition in Ii+ and Ii minus cells and confirm that recognition of the CD1-lipid antigen complex is TCR alpha beta mediated by conferring recognition by transfection of the TCR genes. Recognition of mycolic acid antigens recognized by T cells may be substantially more diverse than previously appreciated.
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