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3 Loop Docking Governs the Cross-Recognition of Closely Related Peptide:Class I Complexes1
ugich2,*,
*
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021;
Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021; and
Department of Pathology, School of Medicine, Washington University, St. Louis, MO 63130
The TCR recognizes its peptide:MHC (pMHC) ligand by assuming a
diagonal orientation relative to the MHC 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) bound to two closely related MHC class
I molecules, H-2Kb and H-2Kbm8. Previous
studies indicated that the pMHC portion likely to vary in conformation
between the two complexes resided at the N-terminal part of the
complex, adjacent to peptide residues 2–4 and the neighboring MHC side
chains. We found that CTL clones sharing TCR 
-chains exhibited
disparate recognition patterns, whereas those with drastically
different TCR-chains but sharing identical TCR
CDR3 loops
displayed identical functional specificity. This suggested that the
CDR3 loop determines the TCR specificity in our model, the
conclusion supported by modeling of the TCR over the actual
HSV-8:Kb crystal structure. Importantly, these results
indicate a remarkable conservation in CDR3 positioning, and,
therefore, in docking of diverse TCR heterodimers onto variant
peptide:class I complexes, implying a high degree of determinism in
thymic selection and T cell activation.
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