Functional evidence that conserved TCR CDR alpha 3 loop docking governs the cross-recognition of closely related Peptide: Class I complexes

The TCR recognizes its peptide:MHC (pMHC) ligand by assuming a diagonal ori entation relative to the NMC helices, but it is unclear whether and to what degree individual TCRs exhibit docking variations when contacting similar pMHC complexes. We analyzed monospecific and cross-reactive recognition by diverse TCRs of an immunodominant HVH-1 glycoprotein B epitope (HSV-8p) bou nd to two closely related MHC class I molecules, H-2K(h) and H-2K(bm delta) . Previous studies indicated that the pMHC portion likely to vary in confor mation between the two complexes resided at the N-terminal part of the comp lex, adjacent to peptide residues 2-4 and the neighboring MHC side chains. We found that CTL clones sharing TCR beta -chains exhibited disparate recog nition patterns, whereas those with drastically different TCR beta -chains but sharing identical TCR alpha CDR3 loops displayed identical functional s pecificity. This suggested that the CDR alpha3 loop determines the TCR spec ificity in our model, the conclusion supported by modeling of the TCR over the actual HSV-8:K-b crystal structure. Importantly, these results indicate a remarkable conservation in CDR alpha3 positioning, and, therefore, in do cking of diverse TCR alpha beta heterodimers onto variant peptide:class I c omplexes, implying a high degree of determinism in thymic selection and T c ell activation.