Pregnancy requires expanded immunological tolerance in mothers to encompass genetically foreign paternal antigens expressed by the developing fetus and placenta. The Way and Tilburgs Labs investigate how this works at the cellular and molecular level with particular focus on tracking maternal immune cells that specifically recognize fetal and placental antigens. Recent work has shown a selective expansion of maternal CD4 T cells with fetal specificity and immune suppressive properties, called regulatory T cells. The Way Lab is focused on investigating fetal microchimeric cells as an antigen source for driving the persistence of protective immune tolerance in mothers during and after pregnancy. Another active area of research in the Way Lab is investigation of the immune pathogenesis of pregnancy complications triggered by infectious and non-infectious disruptions in fetal tolerance. Projects in the Tilburgs Lab are focused on the interactions of invasive placental HLA-G+ extravillous trophoblasts which express paternal HLA-C allo-antigens and their interactions with maternal NK cells and T cells to establish tolerance and also provide immunity during placental infections. Key questions include if failure of maternal-fetal tolerance or excessive inflammatory responses contribute to the development of pregnancy complications including preterm birth and preeclampsia.
Innate Immunity and Inflammation
The Pasare Lab focuses on understanding the fundamental mechanisms of activation of the innate immune system and its impact on inflammation and adaptive immunity. The main goal of the lab is to understand the intricate interplay and cross-talk between the innate and adaptive immune systems and how they influence one another. In particular, we strive to understand how the innate immune system induces inflammation and the molecular pathways that lead to the resolution of inflammation. We have identified several novel proteins and pathways in cells of both innate and adaptive immune systems and use them as handles to address these questions. We use cutting-edge in vitro and in vivo approaches in our studies that are likely to lead to new targets to treat auto-immunity, inflammatory diseases and cancer.
The Starczynowski Lab is interested in the molecular, cellular, and genetic basis of hematologic malignancies, with a specific focus on myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). MDS is a hematopoietic stem cell (HSC) disorder resulting in abnormal blood cell production and a propensity to progress to AML. Unfortunately, the complexity and heterogeneity of MDS and lack of mouse models has impeded our understanding and treatment of this disease. The long-term objective of the lab is to identify altered genes and signaling pathways, and understand the contribution of these alterations to the pathogenesis of MDS and AML. The overarching goal is to eventually provide novel therapies to patients with myeloid malignancies.
Early Life Development
Newborns receive their first microbial inoculum during vaginal birth. This initial bacterial load shapes the early-life microbiome of the newborn and is also critically important in supporting immune cell development of the newborn. A healthy microbiome of the skin, gut and other mucosal surfaces can protect from development of allergies and autoimmune disease and the Deshmukh Lab has now also demonstrated its importance in immunity to infection. The Deshmukh Lab has identified cellular components and molecular targets by which intestinal commensal bacteria direct development of innate defenses of the lungs. They showed that these bacteria control innate immune cell development, prime the immune response and prepare newborns to fight infections. This relationship between microbiome establishment at birth and the maturation of pulmonary mucosal defenses in the newborn highlights the importance of the neonatal period as a critical window in the development of mucosal immunity. It may also explain how a disrupted microbiome establishment and lung development in prematurely born infants has an enduring effect on host resistance to respiratory infections.
The Divanovic Lab focuses on defining the fundamental processes and mechanisms essential for development and pathogenesis of inflammatory and metabolic diseases. The long-term goal of our research is translational exploitation of newly gained insights. Specific focus is on the interplay among immune, metabolic and epigenetic axes in immune cells and adipocytes as critical regulators of: weight gain (obesity), non-alcoholic fatty liver disease (NAFLD), susceptibility to infection, pregnancy outcomes, and vertical transmission of disease. Execution of our projects employs state-of-the-art technology in both experimental models of disease and primary human samples.
The Alenghat Lab investigates molecular pathways that mediate host-microbe interactions and immune regulation at mucosal surfaces. Ongoing projects explore fundamental biology and epigenetic regulation at the epithelial interface between the mammalian host, commensal microbiota, and pathogenic bacteria. Research in the Alenghat Lab employs both basic science and translational strategies to investigate host-microbiota interactions and how this symbiotic relationship affects intestinal immune homeostasis, infection, and inflammatory bowel disease.
Antimicrobial Host Defense
Mucosal tissues are colonized with microbes that have the potential to cause invasive disseminated infection. This includes important human pathogens such as Staphylococcus aureus and Candida albicans. The Way Lab investigates how the body distinguishes between beneficial colonization that requires immunological tolerance and invasive infection caused by microbes that require swift activation of potent immunological responses. There is particular focus on infection susceptibility in developmental windows such as pregnancy, early newborn period, and aging.
Immunological Memory and Exhaustion
CD8 T cells play an important role in controlling viral infections as well as intracellular bacterial and parasitic infections. It is now clear that CD8 T cells are also involved in immunity against tumors and there is considerable interest in cancer immunotherapy that stimulates CD8 T cell immunity. The Araki Lab is interested in understanding the fundamental mechanisms that regulate generation of CD8 T cell memory and exhaustion. The long-term objective of the lab is to develop the rational approaches to induce highly protective CD8 T cell immunity against infectious pathogens and cancer.
A breakdown of immunologic tolerance appears to be a key feature in allergic diseases. The mechanisms underlying the break of tolerance are not well understood and involve a combination of environmental and genetic factors. The epithelium is the first line of defense against potential insults, providing a physical barrier between the host and the external environment. The importance of epithelial integrity in the development of allergic disease is supported by clinical observations of atopic or allergic march, which is the natural history or typical progression of allergic diseases that often begin early in life. These include atopic dermatitis (eczema), food allergy, allergic rhinitis (hay fever) and asthma. At a barrier breach, harmless antigens may encounter immune cells, potentially leading to production of a danger signal and priming a break in immune tolerance and an allergic response. The Azouz Lab investigates the mechanisms by which protease–protease inhibitor imbalance promotes barrier breaches and loss of immunologic tolerance in the development of allergic diseases.