Biased T-cell receptor usage is associated with allelic variation in the MHC class II peptide binding groove.
A comprehensive analysis was carried out of the tri-molecular complex of peptide, major histocompatibility class II molecule, and T-cell receptor (TcR) involved in the recognition of the promiscuous HA (306-318) peptide, restricted by one of two closely related HLA-DR alleles, HLA-DRB1*0101 and HLA-DRB1*0103. These two DR molecules differ by only three amino acids at positions 67, 70, and 71, in the third variable region of the DRB1 chain. None of the HA (306-318)-specific T-cell clones restricted by these two DR molecules tolerated amino acid substitution at the peptide-binding position 71, despite the fact that the substitution did not interfere with peptide binding. The majority of the DRB1*0103-restricted clones tolerated substitution of the amino acid at the TcR-contacting position 70, while the DRB1*0101-restricted T cells did not. Based usage of TRVA and TRVB segments was observed for the DRB1*0103-restricted clones; in contrast, apparently random usage was seen in the DRB1*0101-restricted T cells. Finally, limiting dilution analysis revealed a lower frequency of T cells reactive with the HA peptide in a DRB1*0103 compared with a DRB1*0101 individual. Taken together these data suggest that biased TcR gene usage may reflect a relatively low precursor frequency of T cells, and the need for clonal expansion of a limited set of high avidity T cells.
Yassine-Diab
B
B
U.395 INSERM, IFR 30 INSERM-UPS-CNRS-CHU, CHU Purpan, Toulouse, France.
Carmichael
P
P
L'Faqihi
F E
FE
Lombardi
G
G
Deacock
S
S
de Préval
C
C
Coppin
H
H
Lechler
R I
RI
D000483:Alleles; D014644:Genetic Variation; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D010455:Peptides / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007376:Interleukin-2; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta