Bursky Scholar

The DeSelm Laboratory uses immune cell engineering approaches to develop better living drugs to combat incurable conditions, particularly solid tumors. Novel chimeric antigen receptors (CARs) are rationally designed to generate a desired target-induced signal in T-cells (CAR T-cells) or myeloid cell (CAR macrophages or CAR Antigen Presenting Cells), that instructs the cell to eliminate the target, orchestrate a larger immune response, or induce a change in the microenvironment that facilitates disease resolution and return to a healthy state.

Research in our laboratory is focused on determining the phenotype, function, and specificity of T cells in neurological disorders. Our overarching goal is to gain novel scientific knowledge in regard to adaptive immune responses in neurological diseases that will help guide clinical practice.

The Shan lab is broadly interested in host immune response to HIV infection. Novel mouse models that contain multiple human gene knock-ins can improve support human hematopoiesis and maturation and survival of human immune cells in the mouse system. Using the novel humanized mouse models, the Shan lab will study virus-specific human T cell and NK cell responses in controlling HIV-1 infection and clearing viral reservoirs. With the state-of-the-art IML Core Lab at the Bursky Center for Human Immunology, the Shan lab will particularly focus on the antigen-specificity of HIV-specific T cells in order to understand the viral evolution under immune pressure and how to develop vaccine strategies to eradicate HIV infection.

The Singh Lab is focused on understanding how T cells can be engineered to enhance their function against cancer. T cells that express chimeric antigen receptors, the first-in-class form of synthetically engineered cell therapy, can cure some patients with aggressive and refractory cancers – changing the way we think about cancer therapy. Despite this breakthrough success, it is clear that the first form of this therapy does not reach its reach potential for most patients. Using both classical and novel techniques, we aim to elucidate the molecular circuitry and gene regulatory networks that lead to failure of engineered T cells. Using this knowledge, we use cutting-edge gene and protein engineering methods to control these regulatory circuits, enabling us to derive precise functionality from engineered cells. Our work integrates immunology, molecular engineering, structural biology and genomics to reveal the underlying biology driving these cells and design the next generation of engineered cell therapies.

The Steed laboratory investigates the cellular and molecular mechanisms by which the host antiviral response is influenced by both commensal and pathogen interactions. Research focuses on using a combination of molecular and cell biologic approaches, in concert with in vitro and animal modeling systems, to establish an understanding of host-commensal-pathogen interactions. Central to our studies is our ability to utilize host genetic strategies to perturb these interactions in order to define precise molecular events in pathogenesis and then apply this knowledge to derive novel insights for treatment strategies.
Our early work demonstrated that genetic and environmental enhancement of type I interferon signaling protects from Influenza pathogenesis. Specifically, this work uncovered the role of microbial metabolism in antiviral immunity and has important clinical ramifications. Given the findings that the microbiota and microbiota-derived metabolites are critical regulators of respiratory viral infection, understanding the impact of the microbiota on the host immune response and tissue reparative programs is an important ongoing focus of the laboratory. Our group has also investigated the immune response to SARS-CoV-2 when the pandemic arose. One translational study used single-cell RNA sequencing to elucidate peripheral blood cell type specific transcriptional signatures that associate with and predict survival in critical COVID-19 ARDS. Subsequent in vitro and small scale animal modeling work demonstrated that the SARS-CoV-2 surface proteins spike and envelope alone activate the interferon signaling pathway in both immune and epithelial cells and induced peribronchial inflammation and pulmonary vasculitis.

Our laboratory focuses on examining pathogenic events responsible for initiating the development of tissue-specific autoimmune diseases. We primarily employ mouse experimental models to mechanistically dissect key factors involved in type 1 diabetes, a deteriorating autoimmune disorder that eventually destroys insulin-producing β-cells in the pancreatic islets. The research projects center on 1) Identifying antigenic targets involved in disease pathogenesis, which not only serves as a platform for activating antigen-specific autoreactive T cells but also can be used as diagnostic and therapeutic targets; 2) Examining the biological behaviors of the tissue innate immune system that finely tunes tissue homeostasis and shapes the phenotypic signatures of localized autoimmunity.
Identify MHC-II epitopes required for initiating type 1 diabetes. We recently identified a specific site in pancreatic β cells, the crinosomes, responsible for generating disease-relevant peptides. Crinosomes are a specific set of vesicles formed by fusion of insulin granules with lysosomes. As an enzyme-rich structure, crinosomes not only generate unique or “cryptic” epitopes from degraded protein segments but also produce neoepitopes formed by post-translational modifications. These immunogenic materials are released into circulation during β-cell degranulation and become an antigen source for sensitizing peripheral lymphoid tissues. We are working on to better understand crinosome biology and apply this knowledge to diagnostic and therapeutic aspects of type 1 diabetes. Using a platform integrating mass spectrometry with immunological characterization, we are moving forward to determine disease-relevant epitopes in the islets and peripheral blood from humans with type 1 diabetes.
Examine the role of tissue microenvironment in islet biology and autoimmunity. The pancreatic islet is a mini organ essential for maintaining body metabolism. This tissue contains several types of endocrine cells, including the insulin-producing β cells, but only consists of one immune cell, the resident macrophages. Lineage tracing studies indicate that islet macrophages derive from definitive hematopoiesis. The islet macrophages are in intimate contact with β cells, extending long filopodia in between them. Some of these filopodia enter the blood lumen and can capture microparticles. Islet macrophages isolated from different mouse strains (NOD, NOD.Rag1–/–, B6) have a high expression of genes encoding MHC-II, costimulatory molecules, and inflammatory cytokines and chemokines. We consider such an activation state as a self-defensive mechanism for protecting the islets from pathogen infections. However, autoimmune risk can also be precipitated to foster incoming autoimmune responses. We seek to dissect the key factors expressed by the islet macrophages that not only influence β-cell biology during homeostasis but also play a role in the pathogenesis of autoimmune diabetes.