We focus on two main areas of developmental immunology: (1) how the human fetal immune system is specially adapted to prevent, terminate, or down-regulate immune responses in order to create tolerance; and (2) how the transition from fetal to adult immunity influences neonatal responses to antigen challenge and infection. These two areas of interest are united by the hypothesis that, due to persistent tolerogenic fetal developmental programs, the newborn immune system is prone to be tolerant of the stimuli it encounters. Therefore, rather than mounting an adaptive immune response that would lead to clearing an infection, the infant tends to mount responses that may lead to tolerance. We are committed to employing translational strategies to understand the basis of fetal immune tolerance by studying basic molecular and cellular phenomena, with the goal of ultimately utilizing basic discoveries to inform patient-oriented research. Current projects in the lab include:
(1) Molecular regulation of fetal T cell differentiation and function. There is a high degree of maternal microchimerism in the human fetus, which results in the induction of tolerogenic Regulatory T cells (Tregs) that suppress fetal responses against non-inherited maternal alloantigens. Furthermore, fetal and adult T cells appear to arise from unique hematopoietic stem-progenitor cells (HSPCs), resulting in distinct immunologic functions and gene-expression signatures. Utilizing molecular genetic approaches in vitro and in humanized mouse models, we are studying factors that influence the differentiation and function of tolerogenic fetal T cells. The goal of these studies is to better understand mechanisms of fetal tolerance, and to ultimately use these findings to generate novel therapeutic approaches for use in settings where broken tolerance leads to disease, such as autoimmune disease or transplant rejection. We are concurrently developing in vitro models utilizing induced pluripotent stem cell (iPSC) technology to study the process of T cell differentiation.
(2) The influence of fetal T cells on human neonatal immunity. Based on our findings, we hypothesize that newborns are in a state of transition between dominance of tolerogenic fetal T cells and immunogenic adult T cells. If so, the degree to which this transition has occurred at the time of birth would influence how neonates respond to antigenic challenge and infection. We have developed assays to measure the relative abundance of fetal and adult T cell gene expression in umbilical cord blood from newborns. Utilizing these assays, we have shown that there is striking variability in the degree of immune maturation at birth. We are currently engaged in several translational projects to investigate the potential importance of this finding, including:
(a) SILVER (Study of Immune Layering in Vaccine Effector Responses). This study aims to understand how the persistence of tolerogenic fetal T cell responses in the newborn influences both cellular and humoral immune responses to hepatitis B vaccination at birth.
(b) URECA (Urban Environment and Childhood Asthma) Cohort. In collaboration with Dr. James Gern (University of Wisconsin, Madison), we are studying the influence of immune maturation at birth on the development of asthma and atopy.
(c) Premature infants are born during the third trimester of pregnancy (24-36 weeks of gestation), and are therefore at an incomplete stage of immune maturation. We hypothesize that a relative overabundance of tolerogenic fetal T cells predisposes premature infants to serious infection, and poor immunogenic responses to antigens (including vaccines). We are surveying immune development in premature infants in order to create a ‘roadmap’ of immune development during this period. This will facilitate further studies into how the normal process of development may be altered in diseases leading to prematurity (e.g. preterm labor and preeclampsia). This will also allow us to study how the immune system of premature newborns may contribute to their unique predisposition to certain diseases (e.g. sepsis, necrotizing enterocolitis, respiratory distress syndrome, neurologic injury leading to cerebral palsy).