Mark Ansel, PhD
Naive lymphocytes that encounter their cognate antigens differentiate into a variety of immune effector cells under the influence of cytokines and other inflammatory stimuli. Lymphocyte lineage decisions are critical for the development of protective immunity against a great diversity of pathogens, but improper or exaggerated responses also contribute to the development and pathology of autoimmune diseases, chronic inflammation, allergy, and asthma.
The primary experimental system utilized by the laboratory is the differentiation of helper T cells. Their distinct cellular identities (Th1, Th2, etc.) and associated functions are defined by characteristic gene expression programs. We and many others have documented how these programs are controlled by transcription factors, the cis-regulatory DNA elements to which they bind, and epigenetic modifications that constrain chromatin accessibility at those sites.
More recently, we found that the endogenous RNA interference (RNAi) pathway also regulates helper T cell differentiation, as naive T cells lacking Dicer exhibit rapid, unrestrained differentiation into effector cells. MicroRNAs (miRNA) are the best-characterized class of natural short regulatory RNAs. As they differentiate, T cells reset their miRNA repertoire. This rapid change in miRNA expression may be important to allow T cells to change their gene expression programs and develop effector functions.
The major research goals of our laboratory are: i) to define the molecular mechanisms that control miRNA turnover and determine how this process is accelerated in activated lymphocytes; ii) to characterize the expression and function of noncoding RNAs, including miRNAs, in T cell differentiation, and iii) to extend our work beyond in vitro and mouse models to explore how chromatin remodeling and regulatory RNAs contribute to the pathogenic properties of T cells in human asthma.
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 miRNAs. We study how individual miRNA families regulate helper T cell differentiation and immune function, as well as 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 a high throughput nanoscaled pipeline for determining miRNA expression patterns in 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 miRNA repertoire upon activation. This process that involves ubiquitination and degradation of Argonaute proteins, but the signaling mechanisms and the fate of associated miRNAs remains unknown. This rapid change in miRNA expression may be important to allow T cells to change their gene expression programs and develop effector functions.
The major research goals of our laboratory are:
1) To define the molecular mechanisms that control miRNA homeostasis in lymphocytes, and determine how the miRNA repertoire is so dramatically remodeled during T cell activation.
2) To characterize the function of individual miRNAs that regulate T cell differentiation and immune effector functions.
3) To determine how the expression and function of miRNAs contribute to the pathogenic properties of T cells in human asthma.