Yuri Sykulev, M.D., Ph.D.
Associate Professor
Microbiology & Immunology
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| The major goal of my research program is to understand molecular mechanisms of T cell activation. I am building the program along two principal directions. The first direction is to investigate the biochemistry of T cell receptor and other immune receptors involved in antigen recognition by T cells. Having established Drosophila-based expression system to produce soluble analogs of these molecules, we systematically investigate affinity, kinetics and thermodynamics of the reactions involving these receptors. In parallel, we also study behavior of these molecules as they appear at the surface of live cells using modern visualization techniques, such as confocal microscopy and 3D microscopy. An information derived form these experiments promises to shed light on what is now thought to be a hallmark of T cell activation, namely, formation of molecular assemblies located in distinct membrane compartments induced by productive engagement of T cell receptor with an antigen. Various recruitment patterns of the immune receptors to the membrane activating domains are thought to trigger distinct T cell responses and, thus, provide an explanation for essential flexibility in T cell responsiveness, the most intriguing feature of T cell behavior and functions. The second direction aims to contribute to the development of new strategies of T cell vaccination. The significance of these efforts is emphasized by widely accepted believe that the induction of an effective T cell response is necessary and essential for successful host defense against viral or bacterial infection. While many new vaccination strategies are now becoming available, there are no suitable criteria to evaluate the efficacy of T cells raised in response to vaccination. Meanwhile, these criteria would help to distinguish between more or less promising vaccines during clinical trials. Speaking succinctly, it is essential to make a distinction between "good" and "bad" T cells. Quantitative analysis of molecular interactions between the immune receptors that we are studying will be useful for establishment of such criteria. Both directions complement each other and should have both fundamental and practical implications. This research program is supported by research grant from NIH (RO1) and W.W. Smith Charitable Trust Award. Keywords: efficacy of lymphocyte responses, TCR affinity and TCR microenvironment, visualization of T cell activation |
| Selected Publications PubMed Link For Sykulev Y
Anikeeva, N., Lebedeva, T.,Clapp, A.R., Goldman, E.R., Dustin, M.L., Mattoussi., H., and Sykulev, Y. (2006) QuantumDot/Peptide-MHC Biosensors reveal strong CD8-dependent Cooperation Between Selfand Viral Antigens that Augment the T Cell Response. Proc. Natl. Acad. Sci.USA, 103: 16846-16851.
Anikeeva, N., Martinez-Hackert, E., Kalams, S., Walker, B.D., Hendrickson, W. A. and Sykulev, Y. (2006) Structural basis fordegenerate recognition of natural HIV peptide variants by cytotoxic lymphocytes. J Biol. Chem., 281: 20205-20212.
Lebedeva, T., Dustin, M.L, and Sykulev, Y. (2006) Target cellscontributions to killing through ICAM-1 organization and signaling. In AntigenPresenting Cell (Eds H. Kropshofer & A.B. Vogt), Wiley-VCH, Weinheim, pp.199-206.
Norris,P.J., Stone, J.D., Anikeeva, N., Heitman, J.W., Wilson, I.C., Hirschkorn, D.F.,Clark, M.J., Moffett, H.F., Cameron, T.O., Sykulev,Y., Stern, L.J., Walker, B.D. (2005) Antagonismof HIV-specific CD4+ T cells by C-terminal truncation of a minimumepitope. Molecular Immunology, 43:1349-57.
Lebedeva, T., Dustin, M., and Sykulev, Y. (2005) ICAM-1 co-stimulates target cells facilitating antigen presentation. Current Opinion in Immunology, 17:251-258
Nadia Anikeeva, Kristina Somersalo, Tasha N. Sims, V. Kaye Thomas, Mike L. Dustin and Sykulev, Y. (2005) Distinct role of LFA-1 in effective cytolytic activity of cytotoxic T lymphocytes.Proc. Natl. Acad. Sci. USA, 102: 6437-42.
Lebedeva, T., Anikeeva, N., Kalams, S.A., Walker, B.D., Gaidarov I., Keen, J. H., and Sykulev, Y. (2004) MHC-I-ICAM-1 interactions on the surface of target cells: implication for antigen presentation to cytotoxic T lymphocytes. Immunology, 113: 460-471.
Mareeva, T., Lebedeva, T., Nadja Anikeeva, N., Manser, T. and Sykulev, Y. (2004) Antibody specific for a peptide-MHC complex: is it TCR-like?J. Biol. Chem., 279: 44243-44249.
Somersalo, K., Anikeeva, N., Tasha N. Sims, Verda K. Thomas, Roland K. Strong, Thomas Spies, Lebedeva, T., Sykulev, Y., and Dustin, M.L. (2004) Cytotoxic T lymphocytes form an antigen independent ring junction.J. Clinical Investigation, 113: 49-57.
Anikeeva, N., Lebedeva, T., Kalams, S. and Sykulev, Y. (2003) Soluble HIV-specific T-cell receptor: expression, purification and analysis of the specificity. J. Immunol. Methods, 277: 75-86.
Anikeeva, N., Lebedeva, T., Krogsgaard, M., Tetin, S. Y., Martinez-Hackert, E., Kalams, S., Davis, M.M., and Sykulev, Y. (2003). Distinct molecular mechanisms account for the specificity of two different T-cell receptors. Biochemistry, 42:4709-4716.
Philip J. Norris, Marina Sumaroka, Christian Brander, Howell F. Moffett, Steven L. Boswell, Tam Nguyen, Yuri Sykulev, Bruce D. Walker, Eric S. Rosenberg (2001). Multiple effector functions mediated by HIV-1-specific CD4+ T cell clones. J. Virol., 75: 9771-9779.
Kageyama, S.,. Tsomides, T.J., Fukusen, N., Papayannopoulos, I. A., Eisen, H. N., and Sykulev, Y.(2001).Potent cytolytic response by a CD8+ CTL clone to multiple peptides from the same protein in association with an allogeneic class I MHC molecule. J. Immunol., 166:3028-3034.
Sykulev, Y. (2000). From T-cell receptor ligation to effector functions: affinity, kinetics and pattern recognition. The Immunologist, 9, No 3, 215-221.
Sykulev, Y., Vugmeyster, Y., Brunmark, A., Ploegh, H. L., and Eisen, H.N. (1998). Peptide antagonism and T-cell receptor interactions with peptide-major histocompastibility (MHC) protein complexes.Immunity, 9, 475-483.
Delaney, J., Sykulev, Y., Eisen, H., and Tonegawa, S. (1998). Difference in the level of expression of class I MHC proteins on thymic epithelial and dendritic cells influence the decision of immature thymocytes between positive and negative selection. Proc. Natl. Acad. Sci. USA, 95, 5235-5240.
Eisen, H.N., Sykulev, Y. and Tsomides, T.J. (1996).The antigen-specific T-cell receptors and their reactions with natural ligands: complexes formed by peptides with major histocompatibility complex (MHC) proteins.Adv. Prot. Chem., vol. 49, pp. 1-56, Academic Press, San Diego.
Sykulev, Y., Joo, M., Vturina, I., Tsomides, T.J., and Eisen, H.N. (1996).Evidence that a single peptide-MHC complex on a target cell can elicit a cytolytic T cell response, Immunity, 4, 565-571.
Sykulev, Y.K., Cohen, R.J., and Eisen, H.N. (1995).The law of mass action governs antigen-induced cytolytic activity of CD8+cytotoxic T lymphocytes.Proc. Natl. Acad. Sci. USA,92: 11990-11992
Sykulev, Y., Brunmark, A., Tsomides, T.J., Kageyama, S., Jackson, M., Peterson, P.A., and Eisen, H.N. (1994).High-affinity reactions between antigen-specific T-cell receptors and peptides associated with allogeneic and syngeneic major histocompatibility complex class I proteins. Proc. Natl. Acad. Sci. USA,91: 14487-14491.
Sykulev, Y., Brunmark, A., Jackson, M., Cohen, R.J., Peterson, P.A., and Eisen, H.N. (1994).Kinetics and affinity of reactions between an antigen-specific T-cell receptor and peptide-MHC complexes. Immunity, vol. 1: 15-22. |
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