Nature Immunology
- 7, 1191 - 1199 (2006)
Published online: 15 October 2006; | doi:10.1038/ni1401
Interface-disrupting amino acids establish specificity between T cell receptors and complexes of major histocompatibility complex and peptideEric S Huseby1, Frances Crawford1, Janice White1, Philippa Marrack1, 2, 3 & John W Kappler1, 2, 41
Howard Hughes Medical Institute and Integrated Department of Immunology, National Jewish Medical and Research Center, Denver, Colorado 80206, USA. 2
Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. 3
Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. 4
Department of Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Correspondence should be addressed to Philippa Marrack marrackp@njc.org T cell receptors (TCRs) bind complexes of cognate major histocompatibility complex (MHC) and peptide at relatively low affinities (1–200  M). Nevertheless, TCR-MHC-peptide interactions are usually specific for the peptide and the allele encoding the MHC. Here we show that to escape thymocyte negative selection, TCRs must interact with many of the side chains of MHC-peptide complexes as 'hot spots' for TCR binding. Moreover, even when the 'parental' side chain did not contribute binding affinity, some MHC-peptide residues contributed to TCR specificity, as amino acid substitutions substantially reduced binding affinity. The presence of such 'interface-disruptive' side chains helps to explain how TCRs generate specificity at low-affinity interfaces and why TCRs often 'accommodate' a subset of amino acids at a given MHC-peptide position.
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