The structural dynamics and energetics of an immunodominant T cell receptor are programmed by its Vbeta domain.
Immunodominant and public T cell receptor (TCR) usage is relatively common in many viral diseases yet surprising in the context of the large naive TCR repertoire. We examined the highly conserved Vbeta17:Valpha10.2 JM22 T cell response to the influenza matrix peptide (58-66)-HLA-A*0201 (HLA-A2-flu) through extensive kinetic, thermodynamic, and structural analyses. We found several conformational adjustments that accompany JM22-HLA-A2-flu binding and identified a binding "hotspot" within the Vbeta domain of the TCR. Within this hotspot, key germline-encoded CDR1 and CDR2 loop residues and a crucial but commonly coded residue in the hypervariable region of CDR3 provide the basis for the substantial bias in the selection of the germline-encoded Vbeta17 domain. The chances of having a substantial number of T cells in the naive repertoire that have HLA-A2-flu-specific Vbeta17 receptors may consequently be relatively high, thus explaining the immunodominant usage of this clonotype.
Ishizuka
Jeffrey
J
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Stewart-Jones
Guillaume B E
GB
van der Merwe
Anton
A
Bell
John I
JI
McMichael
Andrew J
AJ
Jones
E Yvonne
EY
D020816:Amino Acid Motifs; D000818:Animals; D018360:Crystallography, X-Ray; D015234:HLA-A Antigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000276:immunology*
D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D050505:Mutant Proteins; D021122:Protein Subunits; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014763:Viral Matrix Proteins