Increased peptide promiscuity provides a rationale for the lack of N regions in the neonatal T cell repertoire

Abstract

Making use of mice deficient for terminal deoxynucleotidyl transferase (TdT) expression and a random peptide library, we have examined the diversity and peptide specificity of the neonatal T cell repertoire specific for a single H-2D b-restricted peptide. Consistent with the predicted decrease in repertoire diversity, polyclonal CTL lines and individual clones from different TdT° mice are more similar to each other than those from different wild-type mice in terms of their finger-prints of cross-reactivity to the library and their TCR sequences. We have also found that several TdT° CTL clones cross-react with many more library peptides than wild-type CTL clones. In a few instances, the degree of peptide promiscuity correlates with TCR sequence characteristics such as N region addition and homology-directed recombination, but not CDR3 loop length. Based on epitope titrations for each clone, TCR affinity for antigen is consistently high; thus, this reduced specificity for peptide may coincide with an accentuated affinity for the α helices of the MHC. Peptide promiscuity in the neonate may allow the relatively small numbers of T cells in the periphery to protect against a broader range of pathogens.