New biological methodologies have enabled definition of cross-reactive peptides using high throughput screens against a series of TCR molecules and some can screen whole cells ( 5– 14). Methods to accurately predict biological specificity or cross-reactivity would have profound clinical, therapeutic and pharmaceutical applications in designing cellular therapies for fighting cancer, autoimmune and infectious diseases. As yet it is not possible to, (a) predict TCRs recognizing a given antigen, or (b) predict antigens recognized by a given TCR.
However, the picture is far from complete. Recent biological and computational advances to screen antigenic peptides and profile TCR repertoires have greatly improved our understanding of the TCR:pMHC interaction. Thus, TCR recognition of pMHC complexes is both cross-reactive, given the high number of total epitopes that could be bound, and at the same time, highly specific considering the low frequency of epitopes that can be recognized by a given TCR. However, it has also been illustrated that once a TCR reacts with a specific peptide-MHC complex, the probability of it reacting with another randomly chosen peptide reduces to ~10 −4 ( 4). In fact, it has been proposed that a single TCR can recognize 10 4-10 7 different MHC-associated epitopes ( 2). The idea was first postulated by Matzinger and Bevan ( 1) and later gained traction via Don Mason who challenged the dominant clonal selection theory arguing a highly incompetent immune system if a TCR was able to recognize only a single pMHC complex ( 2), and Andrew Sewell who empirically measured the necessity of cross-reactivity given the insufficient number of TCRαβ to protect against a wide spectrum of pathogen by comparing the number of potential foreign pMHC complexes a T cell might encounter and the number of TCRs available ( 3).Īlthough it is known that T cells can recognize peptide and non-peptide antigens, it is now well-accepted that peptide-specific TCRs exhibit high levels of cross-reactivity. Unfortunately, the mechanisms underpinning cross-reactivity and antigen specificity of peptide-specific TCRs remain puzzling, and leaves the community with an incomplete picture of T cell recognition.Ĭross-reactivity is defined as the capacity of a TCR to recognize more than one peptide-MHC molecule. A better understanding of TCR:pMHC interaction is required to be able to harness adaptive T cell immunity effectively for vaccines and therapeutics. Specific molecular interactions between heterodimeric T cell receptors (TCRs) and their cognate peptide-MHC (pMHC) ligands contribute to the nature of ensuing adaptive immune response. We further underscore the close inter-relationship of these two interconnected notions and the need to investigate each in the light of the other for a better understanding of T cell responsiveness for the effective clinical applications. We discuss current experimental and computational approaches to investigate cross-reactivity and antigen-specificity of TCRs and highlight how integrating kinetic, biophysical and structural features may offer valuable insights in modeling immunogenicity.
Herein, we review recent developments in predicting cross-reactivity and antigen specificity of TCR recognition.
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