The application is for a Physician Scientist Award to an M.D. who has completed three years of postgraduate residency training in internal medicine and is presently in a rheumatology fellowship program. The applicant plans to spend 100% of his effort over the next five years on the training program described, which includes didactic course work and laboratory training. The research aspect of the training program proposes to extend the novel preliminary observations made in this laboratory characterizing CD1, a newly recognized family of antigen presenting molecules encoded outside the major histocompatibility (MHC) locus on chromosome 1. The 5 homologous genes encoded in the human CD1 locus display overall structural similarity with MHC class I and class II molecules, yet contain little specific sequence homology in the putative peptide binding grooves. Our preliminary studies have shown that these nonpolymorphic MHC-like glycoproteins are ligands for autoreactive CD4- CD8-double negative (DN) T cells, and serve as restriction elements for the specific recognition of microbial antigens by this same T cell subset. Increased numbers of DN T cells are seen in both human autoimmune disease patients and in mouse models of autoimmune disease. These facts, together with our own observations that (1) CD1c molecules are upregulated in RA synovium, (2) T cells autoreactive to CD1c are found in RA synovium and that (3) CD1 autoreactive DN T cell clones have been isolated from patients with SLE, all suggest a possible role for CD1 in autoimmune disease. We now propose 3 aims.
In Aim 1 we will identify self and foreign antigens presented by CD1 by immunopurifying CD1 molecules from either microbial pulsed or unpulsed CD1+ cells, and the eluting and microsequencing the CD1 bound peptides.
In Aim 2 we will identify the CD1 intracellular pathway of assembly and antigen presentation using biochemical techniques, immunofluorescence microscopy and immunogold staining with electron microscopy.
In Aim 3 we will specifically assess the tissue expression of CD1 in 3 important autoimmune disease known to be associated with abnormalities of DN T cells, and them determine the precursor frequencies by limiting dilution analysis of CD1 autoreactive T cells in the affected individuals, comparing these results with data in normals. These studies should provide insights into both the normal biology of CD1 and DN T cells and their altered role in autoimmune disease.
| Beckman, E M; Melian, A; Behar, S M et al. (1996) CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family. J Immunol 157:2795-803 |
