A structural difference limited to one residue of the antigenic peptide can profoundly alter the biological outcome of the TCR-peptide/MHC class I interaction.
The vesicular stomatitis virus (VSV) octapeptide RGYVYQGL binds to H-2K(b) and triggers a cytotoxic T cell response in mice. A variant peptide, RGYVYEGL (E6) with a glutamic acid for glutamine replacement at position 6 of the VSV peptide, elicits a T cell response with features that are quite different from those elicited by the wild-type VSV peptide. The differences found in the nature of the T cells responding to the E6 peptide include changes in both the V beta elements and the sequences of the complementarity-determining region 3 loops of their TCRs. Further experiments found that the E6 peptide can act as an antagonist for VSV-specific T cell hybridomas. To determine whether these differences in V beta usage, complementarity-determining region 3 sequences, and the switch from agonism to antagonism are caused by a conformational change on the MHC, the peptide, or both, we determined the crystal structure of the variant E6 peptide bound to H-2K(b). This structure shows that the only significant structural difference between H-2K(b)/E6 and the previously determined H-2K(b)/VSV is limited to the side chain of position 6 of the peptide, with no differences in the MHC molecule. Thus, a minor conformational change in the peptide can profoundly alter the biological outcome of the TCR-peptide/MHC interaction.
Thomson
C T
CT
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Kalergis
A M
AM
Sacchettini
J C
JC
Nathenson
S G
SG
D019943:Amino Acid Substitution / Q000276:immunology*; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000378:metabolism*; D003460:Crystallization; D006183:H-2 Antigens / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology
D000956:Antigens, Viral; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D008024:Ligands; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell