MicroRNAs, transcription factors, and epigenetic regulation shape the gene expression programs that determine cell identity and function. The Ansel lab studies how these molecular mechanisms work together to control lymphocyte development, differentiation, and function in immunity.
We use in vitro cell differentiation systems, mouse genetics, disease models, and high dimensional cellular and molecular analyses in human biospecimens to unravel the regulatory networks that underlie immunity and immune pathology, especially allergy and asthma.
Lymphocyte lineage decisions and the deployment of their effector functions are critical for the development of protective immunity against a great diversity of pathogens. However, improper or exaggerated responses underlie the pathogenesis of autoimmune diseases, chronic inflammation, allergy, and asthma. Our primary experimental system is the differentiation of helper T cells, the central coordinators of adaptive immune responses. Upon immune activation, naïve CD4+ T cells can differentiate into several different helper T cell effectors subtypes (e.g. Th1, Th2, Th17, iTreg, Tfh, etc.). These lineages are defined by their characteristic gene expression programs and mediate distinct immune functions. These gene expression programs are controlled by external factors that derive from other cells or the environment, signaling-induced and lineage-specific transcription factors, epigenetic regulation of transcriptional responses, and posttranscriptional mechanisms, including RNA-binding proteins and miRNAs. The depth of our knowledge about the networks that control helper T cells makes them an attractive model for studying basic mechanisms of gene regulation.
Active projects in the laboratory mostly focus on RNA regulation of immune cell programming. We study how individual miRNA families regulate lymphocyte differentiation and immune function, and the regulation of the miRNA pathway itself during immune responses. Naive CD4+ T cells that cannot produce any miRNAs exhibit reduced cell division and survival in response to immune stimuli. Surprisingly, they also undergo rapid unrestrained differentiation into effector cells. We have developed a screening technology that allows us to rapidly determine which specific miRNAs regulate each of these T cell behaviors, and pipelines for determining miRNA expression patterns in very small clinical samples (such as sorted T cell subsets from the airways of human asthmatic subjects, serum, sputum, and other sources of extracellular miRNAs, etc.). In addition, we discovered that T cells rapidly reset their small RNA repertoire upon activation. This process involves ubiquitination and degradation of Argonaute proteins and the release of RNAs in extracellular vesicles, but the signaling mechanisms and the fate of associated RNAs remains unknown. Activation-induced changes in regulatory RNA expression affects T cell differentiation and the development of immune effector functions.
The major research goals of our laboratory are:
1) To define the molecular mechanisms that control miRNA homeostasis and extracellular release by lymphocytes, and determine how the miRNA repertoire is so dramatically remodeled during activation.
2) To characterize the function of RBPs and individual miRNAs that regulate T cell differentiation and immune effector functions.
3) To determine how the expression and function of miRNAs contributes to the pathogenic properties of T cells and other immune cells in human asthma.