Antigen exposure in utero: impacts on newborn immunity and infectious diseases

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DESCRIPTION (provided by applicant): Prenatal exposure to microbial antigens can alter neonatal immunity to pathogens, modulate responses to pediatric vaccines, and increase infant susceptibility to infections. Infants born to mothers with P. falciparum infection during pregnancy are at increased risk of developing malaria during infancy, when symptoms are most severe and the risk of dying from the infection is highest. Vγ2Vδ2 lymphocytes, a subset of γδ T cells, mount rapid responses to a broad array of infectious agents, including plasmodia and mycobacteria. Numerous observations suggest the involvement of Vγ2Vδ2 lymphocytes in controlling malaria infection, and P. falciparum infection perturbs their homeostasis in adults contracting malaria for the first time. Vγ2Vδ2 lymphocytes take part in responses to Bacille Calmette-Guérin (BCG), the vaccine against tuberculosis, which is routinely administered to neonates in Sub-Saharan Africa. Vγ2Vδ2 T cell responses are antigen specific, yet MHC unrestricted, so all individuals recognize the same antigens independently of HLA haplotypes. Our preliminary results suggest that placental malaria affects fetal Vγ2Vδ2 lymphocyte phenotype, proliferation and repertoire maturation, attenuating the selection of neonatal pathogen-reactive Vγ2Vδ2 lymphocytes. We hypothesize that strong prenatal antigen stimulation, occurring in particular during placental malaria, induces deletion of pathogen-reactive Vγ2Vδ2 lymphocytes, affecting their repertoire and reactivity in neonates. This might have clinical impacts, contributing to increased malaria morbidity and lower responses to BCG vaccination during infancy. In this perspective, we seek to address two key problems concerning the impact of maternal malaria on fetal immunity and newborn responses to pathogens or pediatric vaccines. First, we want to define the impact of placental malaria on fetal immunity by quantifying changes among γδ T cells. Second, knowing that Vγ2Vδ2 T cells respond both to P. falciparum and BCG, we will test whether changes among Vγ2Vδ2 T cells link placental malaria directly to impaired BCG reactivity in newborn. To achieve these goals, we will compare Vγ2Vδ2 lymphocyte repertoire and responses to P. falciparum and BCG in three exposure groups of neonates and infants: no prenatal exposure to malaria, prenatal exposure to maternal peripheral infection with no placental involvement, and prenatal exposure to placental infection. Our long-term goal is to capitalize on our understanding of immune mechanisms at the fetal-maternal interface for developing intervention strategies to improve responses to pediatric vaccinations.