Abstract
Enrichment for tyrosine in immunoglobulin CDR-H3 is due in large part to natural selection of germline immunoglobulin DH sequence. We have previously shown that when DH sequence is modified to reduce the contribution of tyrosine codons, epitope recognition is altered and B cell development, antibody production, autoantibody production, and morbidity and mortality following pathogen challenge are adversely affected. TCRβ diversity (Dβ) gene segment sequences are even more highly conserved than DH, with trout Dβ1 identical to human and mouse Dβ1. We hypothesized that natural selection of Dβ sequence also shapes CDR-B3 diversity and influences T cell development and T cell function. To test this, we used a mouse strain that lacked Dβ2 and contained a novel Dβ1 allele (DβYTL) that replaces Dβ1 with an immunoglobulin DH, DSP2.3. Unlike Dβ1, wherein glycine predominates in all three reading frames (RFs), in DSP2.3 there is enrichment for tyrosine in RF1, threonine in RF2, and leucine in RF3. Mature T cells using DβYTL expressed TCRs enriched at particular CDR-B3 positions for tyrosine but depleted of leucine. Changing Dβ sequence altered thymocyte and peripheral T cell numbers and the T cell response to an ovalbumin immunodominant epitope. The differences in tyrosine content might explain, at least in part, why TCRs are more polyspecific and of lower affinity for their cognate antigens than their immunoglobulin counterparts.
Highlights
During T and B cell development, V(D)J rearrangement and N addition have the potential to create more than 1016 different T cell receptor (TCR) or immunoglobulin (Ig) antigen binding sites [1, 2]
We have shown that these preferences reflect natural selection of DH sequence followed by subsequent somatic selection when the cells pass through developmental checkpoints [6]
The three reading frames (RFs) in a typical mouse DH have very distinct amino acid signatures, with one RF enriched for tyrosine and two enriched for hydrophobic amino acids, especially leucine in RF3
Summary
During T and B cell development, V(D)J rearrangement and N addition have the potential to create more than 1016 different T cell receptor (TCR) or immunoglobulin (Ig) antigen binding sites [1, 2]. Replacement of TCR-Dβ With Ig-DH will include autoreactive clones that need to be minimized to avoid autoimmune disease These observations highlight some of the pressures under which the adaptive immune system labors to balance competing demands for diversity, protection and efficiency within finite constraints on lymphocyte numbers and time. One method to achieve a balance between these demands would be to program the system to produce preimmune repertoires that facilitate lymphocyte development and function, i.e., to postulate the existence of predetermined, “preferred,” or even locally “optimal” preimmune repertoires To test this hypothesis, we previously scrutinized Ig repertoires from developing B lineage cells and found evidence of consistent preferences in the amino acid composition of the antigen binding site [5]. We sought to test whether similar selective processes were influencing Dβ germline sequence and, T cell receptor diversity, development and function
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