The impact of TCR-CD3 and TCR-pMHC-CD8 interaction on T cell activation

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). 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. In this thesis, two-dimensional kinetics of TCR interaction with CD3 on the extracellular domain was characterized in the present and absence of force, and the impact of mutations affecting TCR-CD3 interaction on TCR antigen recognition was investigated. Based on these findings, TCR-CD3 interaction in the extracellular domain was identified 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, the scope was extended to coreceptor CD8 and the role of force in formation of TCR-pMHC-CD8 trimolecular interaction was investigated in the context of thymocyte selection. The results indicated that force provides a unique readout in functional outcome of thymocytes through differentiating positive selecting ligands from negative selecting ligands. Furthermore, the Lck-dependency in CD8 contribution to the trimolecular interaction was identified, which revealed an inside-out arm of TCR signaling to complement and influence the well-known outside-in path mediated by TCR recognition of pMHC.