Newborn infants are susceptible to serious infections by a wide range of pathogens, especially infants who are born prematurely. This has generally been interpreted to mean that the developing immune system is inactive, ineffective, or uneducated. To the contrary, the human fetal immune system is highly functional, but its primary function appears to be establishing and maintaining immune tolerance.
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. Fetal and adult T cells appear to arise from unique, developmentally restricted hematopoietic stem cell (HSC) populations, 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 direct the differentiation of, and mediate functional responses in 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 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).