Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

UMMS Affiliation

Program in Bioinformatics and Integrative Biology; Department of Biochemistry and Molecular Pharmacology

Publication Date


Document Type



Biochemistry, Biophysics, and Structural Biology | Bioinformatics | Computational Biology | Immunology and Infectious Disease | Integrative Biology | Systems Biology


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.

DOI of Published Version



J Immunol. 2017 Oct 1;199(7):2203-2213. doi: 10.4049/jimmunol.1700744. Link to article on publisher's site

Journal/Book/Conference Title

Journal of immunology (Baltimore, Md. : 1950)

Related Resources

Link to Article in PubMed

PubMed ID