Distinct sets of alphabeta TCRs confer similar recognition of tumor antigen NY-ESO-1157-165 by interacting with its central Met/Trp residues.
Naturally acquired immune responses against human cancers often include CD8(+) T cells specific for the cancer testis antigen NY-ESO-1. Here, we studied T cell receptor (TCR) primary structure and function of 605 HLA-A*0201/NY-ESO-1(157-165)-specific CD8 T cell clones derived from five melanoma patients. We show that an important proportion of tumor-reactive T cells preferentially use TCR AV3S1/BV8S2 chains, with remarkably conserved CDR3 amino acid motifs and lengths in both chains. All remaining T cell clones belong to two additional sets expressing BV1 or BV13 TCRs, associated with alpha-chains with highly diverse VJ usage, CDR3 amino acid sequence, and length. Yet, all T cell clonotypes recognize tumor antigen with similar functional avidity. Two residues, Met-160 and Trp-161, located in the middle region of the NY-ESO-1(157-165) peptide, are critical for recognition by most of the T cell clonotypes. Collectively, our data show that a large number of alphabeta TCRs, belonging to three distinct sets (AVx/BV1, AV3/BV8, AVx/BV13) bind pMHC with equal antigen sensitivity and recognize the same peptide motif. Finally, this in-depth study of recognition of a self-antigen suggests that in part similar biophysical mechanisms shape TCR repertoires toward foreign and self-antigens.
Derré
Laurent
L
Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, New York, NY, USA.
Bruyninx
Marc
M
Baumgaertner
Petra
P
Ferber
Mathias
M
Schmid
Daphné
D
Leimgruber
Antoine
A
Zoete
Vincent
V
Romero
Pedro
P
Michielin
Olivier
O
Speiser
Daniel E
DE
Rufer
Nathalie
N
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002999:Clone Cells; D017124:Conserved Sequence; D006801:Humans; D008545:Melanoma / Q000276:immunology; D008715:Methionine / Q000737:chemistry; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology; D013912:Threonine / Q000737:chemistry; D014158:Transcription, Genetic
D009363:Neoplasm Proteins; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; C504237:peptide NY-ESO-1 157-165; D013912:Threonine; D008715:Methionine