Singh et al. review the myriad factors defining MHC:peptide::TCR interactions contributing to specificity/cross-reactivity. Electrostatic and other forces between TCR and peptide-MHC involving both hypervariable loops and germline determinants, co-receptor interactions, conformational flexibility, and supramolecular architecture all contribute, highlighting the need to consider the entire TCR-peptide-MHC interface. TCR binding can also be dominated by small peptide “hot-spots”, allowing for large variability in the rest of the peptide.
T cell specificity emerges from a myriad of processes, ranging from the biological pathways that control T cell signaling to the structural and physical mechanisms that influence how TCRs bind peptides and MHC proteins. Of these processes, the binding specificity of the TCR is a key component. However, TCR specificity is enigmatic: TCRs are at once specific but also cross-reactive. Although long appreciated, this duality continues to puzzle immunologists and has implications for the development of TCR-based therapeutics. In this review, we discuss TCR specificity, emphasizing results that have emerged from structural and physical studies of TCR binding. We show how the TCR specificity/cross-reactivity duality can be rationalized from structural and biophysical principles. There is excellent agreement between predictions from these principles and classic predictions about the scope of TCR cross-reactivity. We demonstrate how these same principles can also explain amino acid preferences in immunogenic epitopes and highlight opportunities for structural considerations in predictive immunology.
Author Info: (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556; and.
Author Info: (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556; and. (2) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556; and. (3) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556; and. (4) Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605. (5) Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605. (6) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; brian-baker@nd.edu. Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556; and.
