Professor of Microbiology and Immunology, UNC-CH
PHD - University of Texas, Austin
T Cell Receptor (TCR) Recognition/T Cell Activation
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. Regardless of this lack of structural homology, the receptor is able to recognize these structurally diverse ligands. We have examined these receptors in more detail and 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 with significant implications for T cell selection. We are characterizing the affinity and kinetics of association of a number of variants of the recognized peptides for a clear description of the requirements for optimal T cell activation.
Proteomics and Bioterrorism
Francisella tularensis (F. tularensis), the causative agent of tularemia, is a non-spore forming, facultative intracellular bacterium. The bacterium is highly infectious; as few as 10 bacteria may cause disease. NIAID has classified it a category A pathogen because of its extremely high virulence and because it has been engineered to be resistant to common antibiotics. The bacterium is an extremely dangerous potential bioterrorist agent because it presents like influenza infection in the clinic and because it may be transmitted by inhalation, orally, cutaneously, or via insect bite. Using proteomic approaches, we are examining host:pathogen interactions to determine 1) virulence factors in F. tularensis, 2) host responses in macrophages and hepatocytes, 3) new methods for identification of F. tularensis infection in human blood and 4) the F. tularensis proteome. These aims will allow for a new understanding of the pathology of the bacterium and generate new targets for the design of therapies in the event of a bioterrorist event using F. tularensis.
- Gakwaya R, Li X, Wong YL, Chivukula S, Collins EJ, Evans JJ. Examining the collision-induced decomposition spectra of ammoniated triglycerides. III. The linoleate and arachidonate series. Rapid Commun Mass Spectrom. 2007;21(20):3262-8
- Miller PJ, Pazy Y, Conti B, Riddle D, Appella E, Collins EJ. Single MHC mutation eliminates enthalpy associated with T cell receptor binding. J Mol Biol. 2007 Oct 19;373(2):315-27. Epub 2007
- Tian S, Maile R, Collins EJ, Frelinger JA. CD8+ T cell activation is governed by TCR-peptide/MHC affinity, not dissociation rate. J Immunol. 2007 Sep 1;179(5):2952-60
- Hess PR, Barnes C, Woolard MD, Johnson MD, Cullen JM, Collins EJ, Frelinger JA. Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin. Blood. 2007 Apr 15;109(8):3300-7. Epub 2006
- Collins EJ, Burgoyne RW, Wagner CA, Abbey SE, Halman MH, Nur ML, Walmsley SL. Lipodystrophy severity does not contribute to HAART nonadherence. AIDS Behav. 2006 May;10(3):273-7
- Maile R, Pop SM, Tisch R, Collins EJ, Cairns BA, Frelinger JA. Low-avidity CD8lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8hi T cell responses to the same antigen. Eur J Immunol. 2006 Feb;36(2):397-410
- Li X, Collins EJ, Evans JJ. Examining the collision-induced decomposition spectra of ammoniated triglycerides as a function of fatty acid chain length and degree of unsaturation. II. The PXP/YPY series. Rapid Commun Mass Spectrom. 2006;20(2):171-7
The University of North Carolina at Chapel Hill
Campus Box # 7290
Chapel Hill, NC 27599