Comparative sequence analysis of the human T cell receptor TCRA and TCRB CDR3 regions

There is increasing experimental and structural support for the idea that the T cell receptor CDR3 region makes primary contact with the peptide held in the MHC groove. As part of the efforts to understand this critical region of the TCR more fully, we have cloned and sequenced several hundred human TCR transcripts and made an analysis of the amino acids found in the CDR3 region. The length of the CDR3 region is found to be relatively conserved and similar in both TCRA and TCRB sequences. In contrast, the amino acid contribution from individual gene segments varies between the TCRA and TCRB transcripts with the longer TCRAJ segment largely making up for the lack of the D segment in the TCRA gene. Amino acid usage in the CDR3 region is nonrandom with a predominance of charged or polar residues in the TCRA transcript and a majority of glycines in TCRB. Analysis of CDR3 sequence in TCR transcripts cloned from antigen-specific cytotoxic T cells reveals differences in the pattern of amino acid conservation for both chains. The TCRA CDR3 region shows less length conservation than TCRB, but selection for particular TCRAJ segments is marked. In contrast, TCRBV segments are highly conserved and are associated with an amino acid motif in the N region. These findings reveal the different mechanisms that are used by the TCRA and TCRB genes to generate diversity in the CDR3 region and raise the possibility that the two chains may play nonequivalent roles in antigen selection.