Multi-tissue architecture of the adaptive immune receptor repertoire in the cynomolgus macaque

The adaptive immune receptor repertoire (AIRR), consisting of B and T cell receptors (BCRs and TCRs), is critical for human health, and the constitution of the AIRR is tissue-specific. However, the similarity of AIRRs in different tissues, especially with respect to BCR isotypes, remains unclear. Because it is extremely hard to acquire multi-organ tissues from human donors, we investigated the AIRR architecture of the cynomolgus macaque (CM) – the predominant non-human primate model in biomedical research. Using ultra-deep TCR and isotype-specific BCR repertoire sequencing from 22 and 25 tissues, respectively, in three CMs, we revealed 85 novel IGHV allele candidates, 57 of which were verifiable using Sanger sequencing, and 117 TRBV allele candidates. These novel IGHV and TRBV alleles are specific to individual CMs, which suggests high genetic heterogeneity. We also found heterogeneous patterns of V gene usage that varied by individual, isotype (for BCRs only), tissue group, and tissue. The large and small intestines of the CMs contained a high number of intra-group shared clones, but fewer shared clones were identified in other tissues, suggesting a heterogeneous distribution of TCR and BCR repertoires. Importantly, most of the public clones are shared between tissues and have considerable similarity to those of humans. We also observed significantly higher mutation burdens in the public clones and the inter-tissue shared IgM and IgD clones, which suggests that these clones are targeting common antigens. This study reveals the extensive heterogeneity of the AIRRs at the individual, tissue group, and tissue levels and has broad fundamental and clinical implications. The data generated here will serve as an invaluable resource for future studies on adaptive immunity in health and diseases.