CDR3 length in antigen-specific immune receptors.

Abstract

SummaryIn both immunoglobulins (Ig) and T cell receptors (TCR.), the rearrangement of V, D, and J region sequence elements during lymphocyte maturation creates an enormous degree of diversity in an area referred to as the complementarity determining region 3 (CDR3) loop. Variations in the particular V, D, and J elements used, precise points of recombination, and random nucleotide addition all lead to extensive length and sequence heterogeneity. CDR3 loops are often critical for antigen binding in Igs and appear to provide the principal peptide binding residues in TCR.s. To better understand the physical and selective constraints on these sequences, we have compiled information on CDR3 size variation for Ig H, L (K and X) and TCR a,/3, 3`, and 6. Ig H and TCR 6 CDR3s are the most variable in size and are significantly longer than L and 3' chains, respectively. In contrast, TCR a and 8 chain distributions are highly constrained, with nearly identical average CDR3 lengths, and their length distributions are not altered by thymic selection. Perhaps most significantly, these CDR.3 length profiles suggest that 3'//~ TCILs are more similar to Igs than to o~/8 TCR.s in their putative ligand binding region, and thus 3"/6 and ol/8 T cells may have fundamentally different recognition properties. S Pecific vertebrate immune responses are initiated by B andT lymphocytes via Igs and TCRs, respectively. Although x-ray crystal structures are available only for Igs, TCRs are betieved to share a similar tertiary and quaternary structure (1-3). Antigen-specific immune receptors confer specificity against a wide variety of potential pathogens by recombination of V, D, andJ elements into a single Ig or TCR. variable domain-encoding exon (4). Ig L (K and )x), TCR o~ and TCR q/chains utilize only V and J gene elements, whereas Ig H, TCR/3, and TCR 6 also employ one or more D elements. X-ray structural analysis of antibody-antigen complexes shows that one or both of the CDR3 loops of Ig H and L chains are always involved in antigen contact (4). Similarly, the CDR3s of both a and/3 TCR. chains seem critical for peptide recognition (5, 6). As a result of variation in numbers of D and J elements used, D element reading frames, junctional diversity, and N region nucleotide addition, the estimated number of possible CDR3 sequences is greatest for 3'/6 TCRs and least for Igs (irrespective of somatic mutation), with a/8 TCRs being intermediate (7).Characterization of the length distribution of CDR3 in different immune receptor chains is of interest for two reasons. First, in computer modelling of antibodies, the length of a given CDR has a profound effect on its shape, with differences of even one amino acid able to produce significant changes in the overall structure (8, 9). Thus, the analysis of CDR3 length variation among different antigen receptors might shed light on structure-function relationships in different immune receptor classes. Second, Igs undergo affinity maturation via somatic mutation, which does not change CDR3 tength. T cel...

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