Browsing by Subject "Binding kinetics"

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Determining the relationship between TCR affinity and T cell response
(2018-08-16) Stevens, Christopher A.; Maynard, Jennifer Ann, 1974-; Georgiou, George; Alper, Hal; Ehrlich, Lauren; Jiang, Ning; Upton, Jason
The T-cell response is a critical component of controlling many cancers and viral diseases and recently developed T-cell based therapies have become very popular and effective treatment methods. Adoptive cell therapy involves the isolation of a patient’s or donor’s T-cells, expansion or modification ex vivo, and then administration into the patient. The recent FDA approval of an adoptive cell therapy involving an engineering antigen receptor has solidified this technique from a passing fad to a legitimate and effective technique for treating cancer. T-cells are able to recognize a vast range of target antigens through the use of a T-cell receptor (TCR) which targets small peptide fragments presented on the surface of diseased cells in the form of major histocompatibility complexes (pMHC). Further improvement of these therapies and methods requires a deeper understanding of how these TCR-pMHC interactions relate to functionality. Cytomegalovirus is a persistent viral infection that can reactivate periodically during periods of immunodepression. Viral control is mediated by a strong T-cell response and it can cause life-threatening complications in immunosuppressed individuals.Additionally, the T-cell response after chronic CMV reactivation becomes focused to a few individual clonotypes bearing ‘public’ TCRs that have shared sequences between individuals and are often high affinity. This makes CMV an excellent model for studying TCR-pMHC interactions. Several attempts to improve functionality of natural TCRs by engineering for higher affinity have resulted loss of specificity or reduced activation. Methods for direct selection of TCRs with improved activity are currently being developed, however they are very limited, whereas there are a variety of methods for affinity maturation of TCRs. A firm understanding of how TCR-pMHC binding affinity relates to activation would greatly benefit all T cell therapies. This work attempts to provide a better understanding of the relationship between TCR-pMHC affinity and T-cell activity by characterizing TCRs engineered in multiple platforms to obtain a range of affinities while maintaining antigen specificity. Additionally, we observe the relationship between affinity and activity of in vivo derived TCRs against CMV to help aid adoptive cell therapies, as well as the development of a vaccine to elicit potent T-cell responses.