Biased T-cell receptor usage is associated with allelic variation in the MHC class II peptide binding groove

Abstract

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.

Cytokine profile, HLA restriction and TCR sequence analysis of human CD4+ T clones specific for an immunodominant epitope of Mycobacterium tuberculosis 16-kDa protein

“…The last two to three residues of the putative CDR3 loops, encoded by the BJ sequence, are normally conserved in their respective J segments, suggesting that their role is probably to help maintain the overall conformation of the CDR3 loops rather than to contact ligand directly [9,10]. Despite the heterogeneity of BV and BJ segments used, certain conserved amino acid sequences were identified in the CDR3 region [11]. A putative common motif R‐L/V‐G/S‐Y/W‐E/D, or at least part of it (highlighted in bold in Table 3), is apparent in 13 of the 18 clones, being absent in clones P2·1, B4·1, B5·1, P5·3 and P6·1.…”

Structure of a Complex of the Human α/β T Cell Receptor (TCR) HA1.7, Influenza Hemagglutinin Peptide, and Major Histocompatibility Complex Class II Molecule, HLA-DR4 (DRA0101 and DRB10401)

“…The interaction between the HA antigen peptide and TCR HA1.7 is dominated by charged interactions between the three lysine residues of HA at position P-1, P3, and P8 and glutamate and aspartate residues in CDR3 ␣ and CDR1 ␤ of TCR HA1.7 (4,25). These charged interactions are conserved in the recognition of the HA peptide by other TCRs (21,(25)(26)(27).…”

“…The interaction between the HA antigen peptide and TCR HA1.7 is dominated by charged interactions between the three lysine residues of HA at position P-1, P3, and P8 and glutamate and aspartate residues in CDR3 ␣ and CDR1 ␤ of TCR HA1.7 (4,25). These charged interactions are conserved in the recognition of the HA peptide by other TCRs (21,(25)(26)(27). Contacts by TCR HA1.7 to these three lysines and to other residues that point upward from the DR1/HA surface (Val309 (P2), Asn312 (P5), and Leu314 (P7) are important for functional binding (21,(27)(28)(29)(30).…”

Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1

“…Several acidic side chains in the Vα and Vβ domain of different αβTCRs have been predicted to interact, by making salt bridges, with the three positively charged lysines in the HA peptide (Ostrov et al ., 1993; Wedderburn et al ., 1995; Yassine‐Diab et al ., 1999). Attempts to model the overall orientation of TCR binding over the HA/DR1 surface using different experiments, however, have given inconsistent results (Wedderburn et al ., 1995; Yassine‐Diab et al ., 1999).…”