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Chenghao ‘Charles’ Ge
Ph.D. Candidate
Dept. of Biomedical Engineering
Georgia Institute of Technology
Title: 2D kinetic study of TCR-CD3 interaction and the role of TCR-pMHC-CD8 trimolecular interaction in T-cell activation
Date: July 14th, 2017 (Friday)
Time: 10:00 AM EDT
Location: Molecular Sciences & Engineering Building (MSE) Room 1201A
Committee:
Dr. Cheng Zhu, Advisor (Dept. of Biomedical Engineering. Georgia Institute of Technology)
Dr. Krishnendu Roy (Dept. of Biomedical Engineering. Georgia Institute of Technology)
Dr. Khalid Salaita (Dept. of Biomedical Engineering. Georgia Institute of Technology)
Dr. Robert Dickson (Dept. of Chemistry, Georgia Institute of Technology)
Dr. Michelle Krogsgaard (Dept. of Pathology, New York University)
Abstract:
T cells play important roles in adaptive immunity through mediating clearance of bacteria, virus, and cancer cells. T cell receptor (TCR) recognizes antigen presented on the surface of antigen presenting cells (APC) in the form of peptide major histocompatibility complex (pMHC). Based on this information, T cells must make fate decisions, such as expansion or differentiation, that are critical to proper T-cell function. TCR does not contain signaling capability by itself. Instead, intracellular signaling is initiated from the signaling motif found on the cytoplasmic tails of neighboring CD3 subunits. Therefore, understanding how TCR and its neighboring CD3 subunits function as a unit is important for deciphering T cell activation and designing therapeutics aimed at shaping T-cell responses. Recently, more evidence has indicated that force is required in TCR-pMHC interaction and T cell activation, and kinetics of interaction under force show different behavior from force-free conditions. Leveraging findings from these recent studies, we have placed strong emphasis on investigating the role of force in TCR triggering and signaling in this thesis.
In this thesis, we first characterized the two-dimensional (2D) kinetics of TCR interaction with CD3 on the extracellular domain in the present and absence of force, and investigated the impact of mutations affecting TCR-CD3 interaction have on TCR antigen recognition. Based on our findings, we identified TCR-CD3 interaction in the extracellular domain to play a unique role of relaying force from the pMHC recognition end to the intracellar signaling end of the TCR complex.
In the second part of the thesis, we extended our scope to coreceptor CD8 and investigated the role of force in formation of TCR-pMHC-CD8 trimolecular interaction in the context of thymocyte selection. We found that force provides a unique readout in functional outcome of thymocytes through differentiating positive selecting ligands from negative selecting ligands. By further probing factors affecting the formation of this trimolecular interaction, we identified the Lck-dependency in CD8 contribution to the trimolecular interaction and integrated our findings as an inside-out arm of TCR signaling to complement and influence the well-known outside-in path mediated by TCR recognition of pMHC.
Overall, our findings provide a deeper understanding of TCR triggering and early signaling from the perspective of TCR-CD3 interaction and outside-in/inside-out loop of signal integration with the common theme of mechanical force as significant factor influencing TCR function on multiple forms.
