620 Mary Ellen Jones Bldg, CB #7290
T cell receptor (TCR) recognition
We have shown that cross-reactivity of TCR of peptide/MHC (pMHC) is similar to antibody cross-reactivity. The pMHC surfaces recognized are not structurally similar and so it disproves the molecular mimicry theory of cross-reactivity. Regardless of this lack of structural homology, the TCR is able to recognize these structurally diverse ligands. We have shown that recognition of MHC that is CD8-independent requires higher affinity between MHC and the TCR to compensate for the loss of interactions. We have produced soluble recombinant TCR and MHC. The crystal structure of the complex of a xeno-reactive TCR and pMHC shows a non-diagonal binding orientation. We have shown that T cell cytotoxicity is not driven by a kinetic mechanism, but is correlated with affinity. We are examining proliferation, cytokine production and TCR downregulation now to determine if these processes follow the same rules.
Molecular architecture of T cell activation
Estimates have suggested that as few as 1 to 10 MHC that a TCR must engage to activate a T cell. The TCR has no inherent signaling capacity and depends on the co-receptor (CD8 or CD4) to escort the src-family kinase lck to the interaction site. We are examining how these three molecules (TCR, MHC and co-receptor) work together to activate T cells? In a new model of co-receptor involvement, we have bred a CD8 knockout with a class II MHC knockout mouse. Unlike in a CD8 knockout mouse, many class I MHC restricted CD4+ T cells are produced. We are currently characterizing this mouse to determine how the co-receptor controls T cell activation and how the TCR is oriented on class I MHC in the absence of CD8 during thymic selection.
Carroll MJ, Gromova AV, Miller KR, Tang H, Wang XS, Tripathy A, Singleton SF, Collins EJ, Lee AL. Direct detection of structurally resolved dynamics in a multiconformation receptor-ligand complex. J Am Chem Soc. 2011 Apr 27;133(16):6422-8.
Matching biochemical reaction kinetics to the timescales of life: structural determinants that influence the autodephosphorylation rate of response regulator proteins. Pazy Y, Wollish AC, Thomas SA, Miller PJ, Collins EJ, Bourret RB, Silversmith RE. J Mol Biol. 2009 Oct 9;392(5):1205-20.
TCR-MHC docking orientation: natural selection, or thymic selection? Collins EJ, Riddle DS. Immunol Res. 2008;41(3):267-94. Review.
Riddle DS, Miller PJ, Vincent BG, Kepler TB, Maile R, Frelinger JA, Collins EJ. Rescue of cytotoxic function in the CD8alpha knockout mouse by removal of MHC class II. Eur J Immunol. 2008 Jun;38(6):1511-21.
Riddle, D, Miller, P, Vincent, B, Kepler, T., Frelinger, JA, Collins, EJ. Diverse, functional T cells in the absence of TCR/coreceptor agreement (2008) E. J Immunol.
Miller,PJ, Pazy, Y., Conti, B. Riddle, D, Biddison, WE, Appella, E and Collins, EJ Single MHC Mutation Eliminates Enthalpy Associated with T Cell Receptor Binding (2007) JMB 273, 315-327
Tian, S., Maile,R., Collins, E.J., and Frelinger , J.A T cell cytotoxicity is governed by TCR-pMHC affinity, not dissociation rate. (2007) J Immunol. 179, 2952-2960.
Hess, PR, Barnes, C. Woolard, M, Johnson, M, Collins, EJ and Frelinger, JA Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein, saporin (2007) Blood 109(8) 3300-3307
Maile, R., Siler, CA, Kerry, SA, Midkiff, KE, Collins, E.J. and Frelinger, JA Peripheral “CD8-tuning” dynamically modulates the size and responsiveness of an antigen-specific T cell pool in vivo” (2005) J. Immunol 174, 619-627.
Maile, R, Pop, SM, Tisch, RM, Collins, E.J. and Frelinger, JA E Low-avidity CD8 lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher-avidity CD8 hi T cell responses to the same antigen. (2005) J. Immunol 36, 397-410.
March of Dimes Basil O’Conner Early Career Award
Department of Microbiology & Immunology
Department of Biochemistry and Biophysics
Center for AIDS Research (CFAR)
Center for HIV/STDs and Infectious Disease (CFID)
Lineberger Comprehensive Cancer Center (LCCC)
Biological and Biomedical Sciences Program (BBSP)
Program in Molecular and Cellular Biophysics