Our lab studies an important immune cell coreceptor called CD8 and host-pathogen interaction with Chlamydia trachomatis, an obligate intracellular bacteria. The human and chimpanzee CD8B gene has acquired new exons that lead to isoforms with different cytoplasmic tails. We are determining functional relevance with potential applications to immunotherapy. For the Chlamydia project we are examining the mechanisms by which host cells respond when infected.
Extensive Research Description
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.
- The human CD8ß M-4 isoform dominant in effector memory T cells has distinct cytoplasmic motifs that confer unique properties. Thakral D, Coman MM, Bandyopadhyay A, Martin S, Riley JL, Kavathas PB. PLoS One. 2013;8(3):e59374. PMID: 23533620
- Nod1, but not the ASC inflammasome, contributes to induction of IL-1ß secretion in human trophoblasts after sensing of Chlamydia trachomatis. Kavathas PB, Boeras CM, Mulla MJ, Abrahams VM. Mucosal Immunol. 2013 Mar;6(2):235-43. PMID: 22763410
- Uric acid induces trophoblast IL-1ß production via the inflammasome: implications for the pathogenesis of preeclampsia. Mulla MJ, Myrtolli K, Potter J, Boeras C, Kavathas PB, Sfakianaki AK, Tadesse S, Norwitz ER, Guller S, Abrahams VM. Am J Reprod Immunol
- The Golgi-associated protein p115 mediates the secretion of macrophage migration inhibitory factor. Merk M, Baugh J, Zierow S, Leng L, Pal U, Lee SJ, Ebert AD, Mizue Y, Trent JO, Mitchell R, Nickel W, Kavathas PB, Bernhagen J, Bucala R. J Immunol. 2009 Jun 1;182(11):6896-906. PMID: 19454686
- Chlamydia trachomatis infection modulates trophoblast cytokine/chemokine production. de la Torre E, Mulla MJ, Yu AG, Lee SJ, Kavathas PB, Abrahams VM. J Immunol. 2009 Mar 15;182(6):3735-45. PMID: 19265152
- Mutation in EGFP domain of LDL receptor-related protein 6 impairs cellular LDL clearance. Liu W, Mani S, Davis NR, Sarrafzadegan N, Kavathas PB, Mani A. Circ Res. 2008 Nov 21;103(11):1280-8. PMID: 18948618
- Differential expression of the human CD8beta splice variants and regulation of the M-2 isoform by ubiquitination. Thakral D, Dobbins J, Devine L, Kavathas PB. J Immunol. 2008 Jun 1;180(11):7431-42. PMID: 18490743
- Thakral, D., Dobbins, J., Devine, L. and Kavathas PB. (2008). Differential expression of the human CD8 beta splice-variants and regulation of the M-2 isoform by ubiquitination. J Immunol. 11:7431-42.
- Devine, L., Thakral, D., Nag, S., Dobbins, J., Hodsdon, M., Kavathas, P.B. (2006) Mapping the binding site on CD8 beta for MHC class I reveals mutants with enhanced binding. J. Immunol. 177:3930-3938.
- Lee SJ, Kavathas PB, Cresswell P (2007) Severe Tryptophan Starvation Blocks Onset of Conventional Persistence and Reduces Reactivation of Chlamydia trachomatis, Infect Immun, 75(11)5105-17