BiophysicalProperties that Influence Optimal Functional Output of TCR Engineered T Cells
Theencounter of the TCR with its cognate peptide-MHC complex (pMHC) is a crucialstep in T-cell activation. One of the most critical parameters, among manyfactors that influence antigen specific T-cell activation, is the biophysicalnature of the TCR-pMHC interaction defined by TCR affinity and avidity and therelationship with antigen density. Current understanding of how these factorsand the interrelationships between them affect functional avidity remainsundefined. To answer this question, we generated an experimental system inwhich all these main parameters of T cell stimulation are controllable usingTCR engineered T cells with single specificity. This unique system allowedunderstanding the interplay between TCR affinity, avidity and antigen densityand their effect on T cell functionality (as measured by cytokine production, Tcell degranulation and cytotoxicity). We found that TCRs with medium affinityand avidity are more functionality in in-vitro and in-vivo experiments. We alsofound that affinity is related to high TCR downregulation and antigen trogocytosiswhich can affect T-cells functionality at high antigen density, these newfinding can explain the deference in functionality between TCRs. The knowledgeobtained in my research could have significant impact in understanding basicT-cell biology and decision making in choose TCR for therapy in response toantigen.
