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 pe ptide, major histocompatibility class II molecule, and T-cell receptor (TcR ) involved in the recognition of the promiscuous HA (306-318) peptide, rest ricted 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 posit ions 67, 70, and 71, in the third variable region of the DRB1 chain. None o f the HA (306-318)-specific T-cell clones restricted by these two DR molecu les tolerated amino acid substitution at the peptide-binding position 71, d espite the fact that the substitution did not interfere with peptide bindin g. The majority of the DRB1*0103-restricted clones tolerated substitution o f the amino acid at the TcR-contacting position 70, while the DRB1*0101-res tricted T cells did not. Biased usage of TRVA and TRVB segments was observe d for the DRB1*0103-restricted clones; in contrast, apparently random usage was seen in the DRB1*0101-restricted T cells. Finally, limiting dilution a nalysis 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 d ata suggest that biased TcR gene usage may reflect a relatively low precurs or frequency of T cells, and the need for clonal expansion of a limited set of high avidity T cells.