Ontogeny of the B Cell Receptor Repertoire and Microbiome in Mice.

The immune system matures throughout childhood to achieve full functionality in protecting our bodies against threats. The immune system has a strong reciprocal symbiosis with the host bacterial population and the two systems co-develop, shaping each other. Despite their fundamental role in health physiology, the ontogeny of these systems is poorly characterized. In this study, we investigated the development of the BCR repertoire by analyzing high-throughput sequencing of their receptors in several time points of young C57BL/6J mice. In parallel, we explored the development of the gut microbiome. We discovered that the gut IgA repertoires change from birth to adolescence, including an increase in CDR3 lengths and somatic hypermutation levels. This contrasts with the spleen IgM repertoires that remain stable and distinct from the IgA repertoires in the gut. We also discovered that large clones that germinate in the gut are initially confined to a specific gut compartment, then expand to nearby compartments and later on expand also to the spleen and remain there. Finally, we explored the associations between diversity indices of the B cell repertoires and the microbiome, as well as associations between bacterial and BCR clusters. Our results shed light on the ontogeny of the adaptive immune system and the microbiome, providing a baseline for future research.

Tumor-reactive antibodies evolve from non-binding and autoreactive precursors.

The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with IgGs. Intratumoral ASCs in HGSOC were both mutated and clonally expanded and produced tumor-reactive antibodies that targeted MMP14, which is abundantly expressed on the tumor cell surface. The reversion of monoclonal antibodies to their germline configuration revealed two types of classes: one dependent on SHMs for tumor binding and a second with germline-encoded autoreactivity. Thus, tumor-reactive autoantibodies are either naturally occurring or evolve through an antigen-driven selection process. These findings highlight the origin and potential applicability of autoantibodies directed at surface antigens for tumor targeting in cancer patients.