Immunological identity redefined by genetically foreign microchimeric cells

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Abstract. Engrained in the conceptual fabric of how interrelated immunological disciplines including autoimmunity, transplantation, tumor immunology and vaccinology are currently viewed is the classical tenet of binary “self” versus “non-self” antigen distinction. However, reliance on genetically homogenous inbred animals in establishing these immunological principles precludes their applicability to individuals in natural outbred populations that ubiquitously encounter genetically foreign antigens during development and reproduction. For example in humans, exposure to genetically foreign maternal tissue beginning in utero consistently primes in offspring tolerance to immunologically discordant non-inherited maternal antigens. Reciprocally, long-lasting tolerance to genetically foreign fetal chimeric cells that express discordant paternal antigens is retained in mothers after pregnancy. These human observations highlight potent immune regulatory pathways engrained within mammalian reproduction that are efficiently masked when developmental and hereditary genetic diversity is artificially eliminated. Therefore, restoring genetic and antigen heterogeneity amongst homologous chromosomes within individuals, and between individuals for mating has exciting potential to unveil fundamental new insights on the pathogenesis of autoimmunity, and new strategies for therapeutically fine- tuning the balance between immune stimulation and suppression. The long-term goal of my research is improved health for infants and children that suffer unduly from communicable infection. Considering infants born prematurely are especially vulnerable to death or long-term morbidity, my laboratory has uniquely re- focused many leading edge tools to investigate maternal-fetal immunological tolerance and the immune- pathogenesis of pregnancy complications triggered by prenatal infection. Central to our approach has been development of innovative reproductive models that recapitulate genetic heterogeneity between individuals, and heterogeneity amongst homologous chromosomes within individuals, naturally encountered in humans and other outbred populations. By probing depots of genetically foreign antigen encountered within the maternal-fetal gestational dyad needed for persistent bi-directional immunological tolerance, we recently identified the remarkable necessity for genetically foreign microchimeric cells in maintaining tolerance in each developmental context. These newly established reproductive benefits demonstrating nature's intent in preserving bi-directional transfer of cells between mother and fetus during pregnancy, and long-term retention of these genetically foreign microchimeric cells in both mother and offspring, pivotally transforms chimeric cells from a curious scientific phenomena to invaluable tools for illuminating how immunological tolerance naturally works. Accordingly, support from the NIH Pioneer Award would be used to launch my laboratory in the new scientific direction investigating the fundamental immunology and molecular cell biology of microchimeric cells.