All cells in the body contain the same DNA sequence, yet they are able to differentiate into unique cell types – such as blood cells or brain cells – to perform specialized functions. This differentiation process is regulated by lineage-specific transcription factors and maintained by epigenetic chemical modifications, which are passed on from cell to cell as they divide. We are interested in studying these processes in the context of cells in the immune system, particularly as they apply to human disease. The main goals of our research are to understand: 1) what are the transcription factors that regulate normal immune cell development?, 2) how is the expression and function of these transcription factors controlled by regulatory DNA elements?, and 3) how does dysregulation of these pathways contribute to the development of human diseases or resistance to immunotherapy?
Cellular heterogeneity underlies all biological processes, for example, variability in immune responses or cancer relapse rates following immunotherapy. We develop and employ novel single cell techniques to understand several key questions: 1) what are the cell types that underlie innate immune responses?, 2) what are the genetic and epigenetic pathways that regulate cellular variation?, and 3) how do single cells interact to coordinate a productive immune response?
Dendritic cells (DCs) are critical targets for enhancing the immune response to vaccines or cancer immunotherapy. We previously identified Zbtb46 as a transcription factor selectively expressed by DCs (Satpathy et al, 2012). We generated Zbtb46-GFP mice, which allowed for identification and visualization of lymphoid-organ and tissue-resident DCs in vivo. Analysis of Zbtb46-GFP mice identified early DC progenitor stages and transcriptional regulators of their development. For example, transcription factors Batf3 and Notch2 specifically regulated the development of the two major DC subsets, CD8+ and CD11b+ DCs, respectively. Using mice deficient in these factors, we were able to dissect functions of each DC subset in the immune response. For example, CD8+ DCs were required for rejection of immunogenic tumors (Hildner et al, 2008), while CD11b+ DCs were required for clearance of intestinal pathogens (Satpathy, 2013). We are interested in further understanding DC development and function in order to hijack these pathways for disease therapy.