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Paula B. Kavathas, PhD
Professor of Laboratory Medicine, Genetics and Immunobiology
Associate Chair for Research
Director, Science Education Outreach Program

TAC S-641A
203-785-6223
paula.kavathas@yale.edu

1972, B.A., University of Wisconsin
1980, Ph.D., University of Wisconsin
Fellowship: Stanford University

Community of Science Biosketch

Gene Regulation: We created transgenic animals with pieces of human DNA from the human CD8 gene complex (alpha and beta genes) and were able to obtain correct developmental expression of the genes. To localize regulatory elements, we performed sequence analysis, DNase I hypersensitivity mapping, and MAR (matrix attachment region) analysis. We identified several striking regions and are performing further transgenic and knockout studies to firmly establish the presence of regulatory elements.

Structure/Funtion Analysis: The CD8 protein interacts with ligands on the outside of the cell (i.e. MHC class I) and with molecules on the inside of the T cell (i.e. tyrosine kinase p56lck, LAT). It also functions as a coreceptor with the T cell receptor forming a complex with MHC class I. Our goal is to understand in molecular terms how the different protein interactions occur and if there are differences between homo (a/a) vs. heterodimeric (a/b) forms of CD8. Taking advantage of crystallographic information, we perform mutational analysis and create models of how the proteins interact.

Immune Response to Chlamydia Trachomatis (Ct): Ct is the most common cause of bacterial sexually transmitted disease (STD) worldwide and of ocular trachoma in developing countries. We are characterizing T cell responses to the major outer membrane protein (MOMP) of Ct, a good vaccine candidate. Using special reagents called tetramers, we were able to detect MOMP-specific T cells in the peripheral blood of infected individuals at frequencies that are significant (0.01-0.20% of CD8+ T cells). We plan to continue to characterize these cells with regard to homing receptors and function and will determine their role in immunity to Ct.

Publications:

Devine, L., Hodsdon, M.E., Daniels, M.A., Jameson, S.C., and Kavathas, P.B. Location of the epitope for ananti-CD8 antibody 53.6.7 which enhances CD8-MHC class I interaction indicates antibody stabilization of a higher affinity CD8 conformation. Immunology Letters 2004;93: 123-130.

Attinger, A., Devine, L., Wang-Zhu, Y., Martin, D., Wang J-H., Reinherz, E.L., Kronenberg, M., Cheroutre, H. Kavathas, P.B. Molecular basis for the high affinity interaction between the Thymic Leukemia (TL) Antigen I and the CD8 molecule. J. Immunol. 2005;174: 3501-3507.

Devine, L., Thakral, D., Nag, S., Dobkins, J., Hodson, M., Kavathas, P.B. Mapping the binding system CD8ab for MHC Class I reveals mutants with enhanced binding. J. Immunol. 2006; 177:3930-3938.

Kim, S.K., Devine, L., Angevine, M., DeMars, R. and Kavathas, P.B. Direct detection and magnetic isolation of Chlamydia trachomatis major outer membrane protein (MOMP)-specific CD8+ CTLs with HLA class I tetramers.

Devine, L., Kieffer, L.J., Aitken, V., and Kavathas, P.B. Human CD8b, but not mouse CD8b, can be expressed in the absence of CD8a as a bb homodimer. J. Immunol. 164:833-838, 2000.

Devine, L., and Kavathas, P.B. Molecular analysis of protein interactions mediating the function of the cell surface protein CD8. Immunol. Res. 19(2-3):201-210, 1999.

Devine, L., Sun, J., Barr, M., and Kavathas, P. Orientation of the Ig-like domains of CD8ab relative to MHC class I. J. Immunol. 162:846-851, 1999.

Kieffer, L.J., Yan, L., Hanke, J.H., and Kavathas, P.B. Appropriate Developmental Expression of Human CD8b in Transgenic Mice. J Immunol. 159:4907-4912,1997.