Immunity in the skin is mediated by T lymphocytes and Langerhans cells. These cells also are central to the pathogenesis of a large number of inflammatory and malignant diseases such as lupus erythematosus, lichen planus, cutaneous T cell lymphoma, and Histiocytosis X. This proposal outlines a career and research plan directed towards an understanding of the differentiation of T lymphocytes. After entering the thymus, developing T cells express a sequence of differentiation antigens. The CD1 family of proteins is expressed on the surface of T cells only during their intrathymic development. The three CD1 glycoproteins are MHC class I-like antigens also found on the surface of Langerhans cells, some eccrine and B cells. These proteins are regulated by inteferons, and appear to share an antithetical regulation with class I genes. The pattern of expression of this multigene family suggests prominent developmental and tissue specific regulatory elements. The studies propose to: (1) isolate and restriction map 5' upstream, 3' downstream, and intron regulatory sequences for the genes; (2) sequence these isolated regions and the exons; (3) isolate map and sequence cDNA and/or genomic clones for two other CD1 genes; (4) prepare constructs of regulatory regions cloned into promoterless CAT plasmids and transfect T and non-T cells to find the promoter of these genes; (5) prepare constructs and transfect T and non-T cells with globin/H4 plasmids to look for tissue-specific, developmental stage specific and interferon inducible enhancers; (6) search for possible enhancer and repressor proteins using gel retardation and DNA footprinting analysis; (7) determine the exact chromosomal location of the CD1 genes; if linked, use pulse-field electrophoresis to determine the linkage map. Completion of these studies will require the investigator to develop expertise in molecular cloning and regulation studies. He then plans to use these techniques as an independent academic investigator to explore the regulation of T cell differentiation and activation molecules in skin diseases. The studies will be carried out under the close supervision of Dr. Cox Terhorst, who will provide support for these studies. The laboratory and institute environment provide all of the equipment necessary for this research and provide extensive opportunity for research education.
| Elder, J T; Reynolds, N J; Cooper, K D et al. (1993) CD1 gene expression in human skin. J Dermatol Sci 6:206-13 |
| Dunn, D A; Gadenne, A S; Simha, S et al. (1993) T-cell receptor V beta expression in normal human skin. Proc Natl Acad Sci U S A 90:1267-71 |
| Bleicher, P A; Balk, S P; Hagen, S J et al. (1990) Expression of murine CD1 on gastrointestinal epithelium. Science 250:679-82 |
