COMBINED EXPERIMENTAL AND MODELING STUDIES REVEAL NEW MECHANISMS IN T CELL ANTIGEN RECOGNITION
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SUMMARY
T cells of the immune system recognize small antigen peptide fragments loaded onto Major Histocompatibility Complex (MHC) molecules through their T Cell Receptor (TCR). The recognition of antigenic pMHC by the TCR is an extremely sensitive and specific process, discriminating as few as a single antigenic pMHC from the self majority while remaining tolerant to uninfected cells. This unique sensitivity and specificity have been intensely studied, but much is still unknown regarding mechanisms surrounding the antigen recognition process. In the following studies, a Horizontal Atomic Force Microscope (HAFM) was developed to assist in parsing this unique behavior. Utilizing this system, periods of upregulated adhesion, called TCR ligand memory, were investigated between 1E6 TCR and a panel of pMHC of varying potency. The strength of these periods of upregulated adhesion, indicative of an upregulated sensitivity to antigen, inversely correlated with antigen potency. Inhibition of proximal signaling molecule Lck decreased the triggering of these periods, but did not significantly affect their duration. Interestingly, membrane cholesterol oxidation by cholesterol oxidase eliminated TCR ligand memory all together. Treatment with cholesterol sulfate, a naturally occurring analog of cholesterol, depleted TCR ligand memory in a dose-dependent fashion. This behavior was simulated to extract estimates of kinetic parameters and showed that TCRs upregulated their kinetics several magnitudes very quickly upon initial antigen recognition. This mechanism is a way to increase antigenic sensitivity and increase antigen rebinding to further cell activation. xiv Additionally, OT-1 double positive thymocytes were probed by pMHC using a Biomembrane Force Probe (BFP) with different ligands under the presence of CD8, a coreceptor which also binds MHC independently of TCR. Negatively selecting ligands resulted in catch-bonds, and positively selecting ligands resulted in slip bonds. This process relied on the kinase activity of Lck. Simulation-based analysis on these data sets indicated that this mechanism was not the result of passive processes. Force induced formation of long-lived bonds, indicating that mechanical forces are priming formation of a larger complex which enhances lifetime. These bonds dominate the average lifetime and result in catch-bond behavior. Simulations of the BFP assay suggest that mechanotransduction by the TCR resulted in active heterodimerization of CD8 and TCR via interactions between intracellular tails of CD3(TCR) and Lck(CD8). This mechanism results in additional upregulation of binding kinetics for increasing antigen capture and rebinding to promote signaling, thereby also increasing antigen sensitivity and discrimination.
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