Due to their unique capacity to recognize a nearly infinite array of antigen variants with exquisite sensitivity, T cells have the potential to eradicte many types of diseases, from those caused by external pathogens to those caused by transformation from within (i.e. cancer). Although it has been shown that T cells can play a key role in the control of tumor progression, tumor-specific T cells almost universally suffer from a poor capacity to recognize tumor antigen due to intricate mechanisms of central and peripheral immune tolerance. It has been established that the avidity of T cells for their target antigen is dictated by the affinity, frequency, and valency of interactions between TCR and cognate peptide-MHC (pMHC). In fact, in order for T cells to undergo full activation and expansion in response to antigen encounter, they must exhibit a high TCR affinity for cognate peptide-MHC (pMHC) (`kinetic proofreading' model), sample the antigen persistently (`serial triggering' model), or acquire high TCR occupancy by pMHC (`valency' model). The purpose of this proposal is therefore to develop a molecular approach that, in a concerted manner, couples the early onset of TCR signaling by cognate pMHC with a surge in pMHC-TCR affinity, with repeated pMHC encounter, and with widespread TCR crosslinking. We hypothesize that-on fusion to pMHC-ANXA5 behaves as a dynamic anchor that tightly engages externalized PS on the plasma membrane of cognate T cells upon TCR signaling, fastening pMHC to this membrane. We infer that in this membrane-tethered form ANXA5 stabilizes pMHC-TCR interactions, facilitates repeated antigen encounter, and prompts extensive TCR crosslinking, thereby instigating the full activation of cognate T cells with a high degree of spatial and temporal control. In this proposal, we will rigorously investigate ANXA5 fusion as a strategy for the activation of low avidity T cells by cognate pMHC. To this end, our specific aims are: 1) To characterize the effect of the ANXA5 dynamic anchor on the activation of low avidity T cells by pMHC, and 2) To characterize the molecular mechanisms by which the ANXA5 dynamic anchor augments activation of cognate T cells by pMHC. The successful implementation of this proposal will introduce unprecedented opportunities for the activation of low avidity T cells, which may lead to the successful clinical management of cancer and intractable infectious diseases.
This project aims to develop a technology that can elicit full activation and expansion of low avidity tumor- specific T cells. The strategy is to develop a molecular approach that, in a concerted manner, couples the early onset of TCR signaling by cognate pMHC with a surge in pMHC-TCR affinity, with repeated pMHC encounter, and with widespread TCR crosslinking, ultimately amplifying signaling through the TCR and resulting in robust activation of low avidity tumor-specific T cells. The successful implementation of this proposal will introduce unprecedented opportunities for the activation of low avidity T cells, which may lead to the successful clinical management of cancer and intractable infectious diseases.
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