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 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-2K(b) and H-2K(bm8). 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 beta-chains exhibited disparate recognition patterns, whereas those with drastically different TCRbeta-chains but sharing identical TCRalpha CDR3 loops displayed identical functional specificity. This suggested that the CDRalpha3 loop determines the TCR specificity 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 CDRalpha3 positioning, and, therefore, in docking of diverse TCRalphabeta heterodimers onto variant peptide:class I complexes, implying a high degree of determinism in thymic selection and T cell activation.
Messaoudi
I
I
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
LeMaoult
J
J
Metzner
B M
BM
Miley
M J
MJ
Fremont
D H
DH
Nikolich-Zugich
J
J
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002999:Clone Cells; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology; D003460:Crystallization; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000276:immunology; D016056:Immunodominant Epitopes / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000276:immunology / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D014759:Viral Envelope Proteins; C040495:glycoprotein B, Simplexvirus