Despite extensive similarity in germline DH and JH sequence, the adult Rhesus macaque CDR-H3 repertoire differs from human

Rhesus macaques (Macaca mulatta) and chimpanzees (Pan troglodytes) are frequently used models for the study and treatment of human infectious diseases, including AIDS. Confidence in the equivalence to human of the humoral immune responses of these higher primates has grown as studies of immunoglobulin germline sequences have documented average identities of 90% or greater to human counterparts. The most variable component of the immunoglobulin heavy chain, complementarity determining region 3 (CDR-H3) is the product of somatic (junctional) as well as germline (combinatorial) mechanisms of diversity. Located at the center of the antigen binding site, CDR-H3 often exerts a dominant role in antibody specificity and affinity. To test whether similarity in germline DH and JH sequence would yield similarity in CDR-H3 composition in the expressed repertoire, we compared IgM CDR-H3 transcripts from Rhesus and chimpanzee blood to human. In fetal Rhesus, the range and mean of CDR-H3 lengths was similar to that observed in fetal human. However, the Rhesus repertoire of adult μCDR-H3 transcripts did not contain the longer hypervariable intervals that humans begin to express late in the second trimester of fetal life. Conversely, the adult chimpanzee repertoire included more long CDR-H3 structures than human. The differences between these adult repertoires reflected fine changes in N addition and terminal nucleotide loss. We conclude that the same mechanisms that refine and shape CDR-H3 diversity during ontogeny can also be used to fine tune and individualize species-specific antibody repertoires despite germline immunoglobulin sequence similarity.