Bobby L. Jones, II; Harry W. Schroeder, Jr., M.D./Ph.D.; and Andre M. Vale, Ph.D. University of Alabama at Birmingham, Birmingham, AL
In both mouse and human, the ability to respond to antigen develops in a controlled, programmed fashion during ontogeny. In both species, this process is associated with fetal restrictions in the composition of immunoglobulin CDR-H3. Although both species restrict their fetal repertoires, the mechanisms differ. In the mouse, fetal CDR-H3s lack N nucleotides, limiting them to germline sequence. In human, however, fetal CDR-H3s contain N nucleotides. Differences between fetal and adult CDR-H3 focus on altered use of DH and JH gene segments, with preferential use of tyrosine-depleted DQ52, the most highly conserved DH between mouse and human, and reduced use of tyrosine enriched JH6. Recent studies of mice limited to the use of a single DH gene segment have shown that the germline sequence of the DH can predetermine the sequence composition of the CDR-H3 repertoire and suggest that normal enrichment for tyrosine might facilitate or optimize humoral immune responses. To test whether a DQ52-containing CDR-H3s might differ significantly in sequence content from the wild type population as a whole, we analyzed 71 DQ52-containing CDR-H3s cloned from adult BALB/c bone marrow and compared them to 53 DQ52-containing CDR-H3s cloned from human fetal tissues. The mouse and human DQ52-specific CDR-H3 repertoires proved to be highly similar in amino acid utilization. When compared to the repertoire as a whole, both proved to be deficient in tyrosine, and enriched for threonine and tryptophan. These studies raise the possibility that that depletion of tyrosine in human fetal CDR-H3s may help restrict immune responses to antigen during early development.