Examining immunological tolerance through the lens of reproduction

Abstract

Abstract Pregnancy is generally considered an “immunological conundrum” whereby a mother must circumvent immunological rules dictating binary “self” vs “non-self” antigen distinction to tolerate her genetically-foreign baby. However, considering reproductive success is the primary biological imperative for all species, it has likely served as an important driver of immune development across mammalian evolution. In other words, reproductive tolerance is not an exception to these rules but serves as a selective pressure continually refining our immune development. To this end, we have begun investigating the long-term impacts of the bi-directional exchange of intact maternal and fetal cells during pregnancy that persist systemically at low, microchimeric levels in mother and child decades after delivery. We believe these genetically-foreign microchimeric cells are not accidental souvenirs of pregnancy, but are instead intentionally preserved to promote tolerogenic memory to both fetal-paternal and non-inherited maternal alloantigens encountered during pregnancy. Thus, we have developed animal pregnancy models and cutting-edge tools that allow selective manipulation of maternal and fetal microchimeric cells together with dynamic tracking of antigen-specific immune responsiveness to these genetically-foreign cells during and after pregnancy. Viewing reproductive success as a strong driver of our immunological evolution, uncovering tolerance mechanisms employed during and after pregnancy will not only inform strategies for amelioration of pregnancy complications but applies in other clinical settings where the ability to regulate immune tolerance is desired (e.g. transplantation, cancer, persistent infection).