Viral escape at the molecular level explained by quantitative T-cell receptor/peptide/MHC interactions and the crystal structure of a peptide/MHC complex.
Viral escape, first characterized for the lymphocytic choriomeningitis virus (LCMV) in a mouse transgenic for the P14 T cell-receptor (TCR), can be due to mutations in T-cell epitopes. We have measured the affinity between the H-2D(b) containing the wild-type and two of its "viral escape" epitopes, as well as other altered peptide ligands (APL), by using BIACORE analysis, and solved the crystal structure of H-2D(b) in complex with the wild-type peptide at 2.75 A resolution. We show that viral escape is due to a 50 to 100-fold reduction in the level of affinity between the P14 TCR and the binary complexes of the MHC molecule with the different peptides. Structurally, one of the mutations alters a TCR contact residue, while the effect of the other on the binding of the TCR must be indirect through structural rearrangements. The former is a null ligand, while the latter still leads to some central tolerance. This work defines the structural and energetic threshold for viral escape.
Tissot
A C
AC
Biochemisches Institut der Universität Zürich, Winterthurerstrasse 190, Zürich, CH-8057, Switzerland.
Ciatto
C
C
Mittl
P R
PR
Grütter
M G
MG
Plückthun
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000302:isolation & purification; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D006183:H-2 Antigens / Q000737:chemistry* / Q000276:immunology* / Q000302:isolation & purification; D064532:Histocompatibility Antigen H-2D; D007108:Immune Tolerance / Q000276:immunology*; D008024:Ligands; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D017433:Protein Structure, Secondary; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D012997:Solvents; D020349:Surface Plasmon Resonance; D013816:Thermodynamics; D014764:Viral Proteins
D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D012997:Solvents; D014764:Viral Proteins; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus