Primary immunoglobulin repertoire development: time and space matter

Abstract

The primary immunoglobulin repertoire develops via opposing forces of expanding diversification balanced by contracting selection mechanisms. The resulting shape is essential for host health and immune fitness. While the molecular mechanisms of Ig diversification have largely been defined, selection forces shaping emerging Ig repertoires are poorly understood. During lifetime, human and mouse early B cell development occurs at distinct locations-beginning in fetal liver before transferring to bone marrow and spleen by the end of gestation. During an early life window of time, the murine gut lamina propria harbors developing immature B cells in proximity to intestinal contents such as commensal microbes and dietary antigens. Location and timing of early B cell development may thus endow neighboring antigens with primary repertoire-shaping capabilities.

Figure 1. Relationships between the timing and location of B cell development and establishment of the immunoglobulin repertoire

During fetal life, primary Ig repertoire generation takes place in the liver before migrating to fetal BM and spleen at the end of the gestation period. B cell development and selection at this stage occurs in the absence of gut microbes and other environmental antigens. After birth, commensal/mutualistic microbial colonization is marked by low diversity, low abundance and instability before weaning [58,68]. In this context, the neonatal Ig repertoire is comprised of maternal Ig and nascent primary Ig repertoire in BM and spleen. At weanling age in mice, B cell development also takes place in the gut LP, alongside a dramatic change in the gut microbiota with the introduction of solid food [58,68]. In this limited window of time, B cell niches and resources are not limiting and it is suggested that most of the emerging B cells greatly contribute to the primary Ig repertoire [29,69] (size of the blue arrows represent the putative relative contribution of each site to the Ig repertoire). Late-infancy and adult gut microbiota are marked by anaerobic species, along with higher diversity, abundance and stability. Modifying factors such as diet, environment, infections, use of antibiotics, and disease conditions influence gut microbiota composition throughout life. BM is the principal site of B cell development in adults, and with aging, BM input of immature B cells decreases and antigen-experienced B cells that have undergone SHM (AID-mediated repertoire) accumulate [70].