Thymic plasma cells as a source of protective natural antibodies in human neonates

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PROJECT SUMMARY Infection is among the leading causes of neonatal deaths worldwide. Serological immunity is considered to be the most effective first line of defense against endemic pathogens. Understanding how this protective immunity develops in early life is essential to identify areas of vulnerability and design strategies to combat neonatal infections worldwide. This area of research however is underexplored. Several recent studies indicate that B cell immunity starts to develop during fetal life. For instance, cord blood IgM present in the cord blood originate exclusively from the fetus. Along the same line, IgG from fetal origin is also present in newborns blood although its exact concentration is masked by the abundance of maternal IgG. Overall, very little is known about the composition and repertoire of innate humoral immunity developed by the unborn child. The source of these natural antibodies in the fetus is also unclear. Liver and spleen are important sites of B cell ontogeny in utero but the differentiation of antibody-producing cells in these two organs during fetal life has not been reported. Our recent work revealed an alternate and rather unexpected source of natural antibodies in newborns. We uncovered that the human thymus at birth contains a significant contingent of antibody-producing PC. This subset is surprisingly heterogenous and includes clones producing all classes and subclasses of immunoglobulin with the exception of IgD. Furthermore, converging lines of evidence support the view that these PC differentiate intrathymically through a mechanism that remains to be fully elucidated. Remarkably, ~7% of neonatal PC reacted to at least 1 of 7 pathogenic and commensal bacteria tested. Neonatal thymic PC were also enriched in clones reactive to apoptotic cells, a hallmark of natural antibodies. Collectively, these findings exposed the human thymus as an unsuspected source of natural antibodies in human newborns. Investigating these thymic PC will therefore provide a rare opportunity to examine how innate humoral immunity develops in humans. Here, we further characterize the composition of neonatal thymic PC populations and more specifically identify predominant clones which were more likely to have contributed to innate serological immunity. Studies will also assess their reactivity profile toward bacteria as well as their protective capabilities. We anticipate these studies will shed new light on this essential component of natural immune defenses against infections in early life. Experiments will be carried out in two specific aims: Aim 1. To characterize Nabs produced by dominant neonatal thymic plasma cells Aim 2. To assess antibacterial activity of Nabs produced by neonatal thymic plasma cells