Research
Health vs disease: how do environmental perturbations lead to immune mediated diseases?
A major research goal of the laboratory is to decode the environmental cues that shape the development and functional maturation of the post-natal immune system and determine how dysregulation can lead to immune-mediated diseases.
Using state of the art single cell ‘omics’, advanced imaging techniques and sophisticated genetically engineered mouse models for tracing and ablation of distinct immune cell lineages, our work aims to decode cellular circuitry between immune and non-immune cells.
Through the study of unique clinical cohorts at Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, our work transitions between laboratory experimental research and human disease focused research.
Early life immune tolerance
How is immune tolerance established in early life and maintained in adulthood?
Dramatic changes in the microbiota and diet during early life pose a challenge to the developing immune system. We are exploring the mechanisms by which the immune system establishes and maintains tolerance to these environmental antigens.
Work from the lab defined the cell types and mechanisms that instruct peripheral regulatory T cell development and tolerance to the gut microbiota during early life. This work identified a novel lineage of antigen-presenting cells, named Thetis cells, enriched in gut lymph nodes during early life. Our studies revealed transcriptional homology between Thetis cells and medullary thymic epithelial cells, highlighting parallels between mechanisms of thymic and peripheral tolerance. These discoveries raise key questions which our work seeks to address:
How does the tissue microenvironment and microbiota regulate Thetis cell differentiation and function?
Do maternal factors shape the development of Thetis cells?
What are the mechanisms by which Thetis cells instruct tolerance to the microbiota?
What is the role of Aire in Thetis cells?
Do perturbations in Thetis cell development and function lead to autoimmune and inflammatory disease?
Inflammation,
tissue repair and regeneration
Dendritic cells in inflammation, tissue repair and regeneration: initiators and resolvers?
Dendritic cells initiate inflammatory responses against pathogens; however, resolution of inflammation and tissue regeneration is critical to restore tissue homeostasis. We have uncovered dendritic cell lineages with complementary roles in tissue repair, tolerance and inflammation. Using a combination of advanced spatial imaging techniques, single cell profiling and computational approaches to decode the cellular circuitry between dendritic cells, immune and stromal cells, our work addresses the following questions:
What are the molecular programs underlying dendritic cell heterogeneity?
What are the signals that shape the balance between dendritic cell subsets within the tissue?
How do distinct dendritic cell microenvironments influence T cell mediated immunity?
What is the role of dendritic cells in resolution of inflammation and tissue repair?
We have established novel genetic models to temporally perturb dendritic cell lineages and our research addresses their role in inflammation, immune tolerance and tissue repair.
Tumor progression, metastasis and cancer immunotherapy
How does the tumor microenvironment influence dendritic cell differentiation and in turn how to intra-tumoral dendritic cells influence tumor growth and metastasis?
Dendritic cells are imprinted by the tissue in which they reside. Through our studies of tissue specific dendritic cell heterogeneity we aim to understand:
How does the site of the tumor, with its distinct repertoire of tissue associated immune cells, shape the tumor immune response?
What are the mechanisms by which distinct dendritic cell subsets regulate tumor growth and metastasis?
As the gatekeepers to T cell mediated immunity, dendritic cells harbor enormous therapeutic potential for cancer immunotherapy. By decoding the distinct functional roles of dendritic cell subsets, our aim is to translate single cell immunology into novel therapeutic approaches for enhanced tumor immunity.
Lack of data on the immune landscape of both healthy pediatric tissues and pediatric solid tumors limits rational use of cancer immunotherapy in children. The Brown Lab is committed to mapping the developing human immune system and its interaction with solid tumors in order to develop novel immunotherapeutic targets in pediatric cancer.