Premium
Engineering T Cell Receptors to Optimize Recognition of Target Antigens
Author(s) -
Riley Timothy,
Baker Brian
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.571.31
Subject(s) - t cell receptor , major histocompatibility complex , peptide , computational biology , t cell , antigen , microbiology and biotechnology , receptor , biology , mhc restriction , chemistry , immune system , immunology , biochemistry
The activation of the adaptive immune response involves the interaction between a T‐cell receptor (TCR) and a peptide from a foreign antigen presented by the Major Histocompatibility Complex proteins (MHC). When measured in solution, TCR affinity for a peptide/MHC is relatively weak (K D values range from 1‐200μM). There is evidence to suggest that binding affinity correlates with in vivo potency, which has led to the generation of several high affinity TCR variants. However, increases in affinity can result in cross‐reactive, off target recognition. The potential negative consequences of TCR cross‐reactivity has led to the suggestion that the most critical property for an engineered TCR is a high affinity, high specific interaction. Structure guided design of TCRs preserves specificity by designing and constructing targeted interactions. Our laboratory has implemented this approach using the Rosetta software suite to optimize TCR‐peptide/MHC interactions. When combined with a custom energy function, this approach was able to identify several affinity‐enhancing mutations in the A6 and DMF5 TCRs, with a strong correlation between predicted and measured changes in binding energy. However, our preliminary data indicates that the approach taken with A6 and DMF5 is not as successful with other TCRs, indicating further development is needed to develop a generally applicable approach for enhancing TCR‐peptide/MHC binding.