Combined experimental and modeling studies reveal new mechanisms in T cell antigen recognition

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Rittase, William Russell
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T cells of the immune system recognize small antigen peptide fragments loaded onto Major Histocompatibility Complex (pMHC) 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 the antigen recognition process. A horizontal atomic force microscope 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 under various pharmacological interventions. This behavior was simulated to extract estimates of kinetic parameters and indicated that TCRs quickly upregulate their kinetics several magnitudes upon initial antigen recognition for antigen recapture. 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. Simulations of the BFP assay suggested that mechanotransduction by the TCR resulted in active heterodimerization of CD8 and TCR via intercellular interactions. These results indicate that the binding kinetics of the TCR and associated molecules are not static as previously considered and actively change to enhance recognition. The implications for future research on the TCR and general molecular kinetics are discussed.
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