The major histocompatibility complex (MHC) class I and class II molecules bind immunogenic peptide antigens and present them to alpha/beta T cells. An analogous antigen presenting function has recently been demonstrated for the non-MHC encoded CD1 molecules by studies performed in the laboratories of the applicants' sponsors. These investigators have shown that in contrast to the presentation of peptide antigens by MHC encoded molecules, CD1 molecules can mediate the presentation of lipid and glycolipid antigens found in the cell walls of mycobacteria. This finding, along with the discovery that CD1 expression in granulomatous lesions from patients with mycobacterial infection correlates with resistance to disease, implies that antigen presentation by CD1 molecules may be playing a significant role in the host response against microbial infections.
The aim of this proposal is to characterize the cellular and biochemical pathways involved in processing and presentation of antigens for recognition by CD1 restricted T cells, and to compare these findings to features established for the well-described MHC class I and class II systems. The applicant plans to demonstrate the mechanisms by which CD1 restricted antigens are presented to T cells. His studies will concentrate on the assembly and intracellular trafficking of CD1 molecules. Initial experiments will establish in vitro systems for the study of CD1 trafficking and assembly and will also determine the steady state localization of CD1 molecules in cultured cells. Subsequent studies will examine the effects of calnexin, beta2m and invariant chain (Ii) on CD1 assembly and intracellular trafficking. These three proteins are known to play key roles in the assembly and trafficking of MHC encoded antigen presenting molecules and preliminary studies performed in the laboratories of the applicant's sponsors indicate that all three are likely to be involved in the assembly, trafficking or antigen presenting function of CD1 proteins. The applicant will dissect the functional roles of these molecules both in biochemical assays and in mutant and genetically engineered cell lines. Where possible, he will compare these results to features established for antigen presentation by MHC class I and class II molecules. In addition, he will also initiate studies to identify the site(s) of CD1 antigen binding and assess the ability of cells to covalently modify or process these unique antigens. All of these studies are included as part of a training program in basic immunology for the applicant of this Physician Scientist Award. This program will include two phases. Phase 1 will emphasize didactic studies and phase 2 will focus on applied research. This program will build upon the applicant's previous training in molecular biology and protein biochemistry, teaching techniques in cellular immunology and cell biology. Concurrently, it will provide a strong theoretical background in basic immunology. With this training the applicant will develop the skills necessary to establish himself as an independent investigator in immunology. At the end of this training program the applicant intends to obtain a faculty position and pursue an academic career in basic research.
