- Li, Y.*, Brauer, P.*, Singh, J., Xhiku, S., Yoganathan, K., Zúñiga-Pflücker, J.C.*, Anderson, M.K.* Targeted disruption in TCF12 reveals HEB as essential for human mesodermal specification and hematopoiesis. Stem Cell Reports. 2017 Sep 12; 9(3): 779-795.
* co-first and co-last authors
- In T.S., Trotman-Grant A., Fahl S., Moore A.J., Chen E.L., Zarin P., Wiest D.L., Zúñiga-Pflücker J.C., Anderson M.K. HEB is required for the specification of fetal IL-17-producing gamma delta T cells. Nature Communications. 2017 Dec 8;8(1): 2004.
- Schrankel C.S., Solek C.M., Buckley K.M., Anderson M.K., Rast J.P. A conserved alternative form of the purple sea urchin HEB/E2-2/E2Atranscription factor mediates a switch in E-protein regulatory state in differentiating immune cells. Developmental Biology. 2016 Aug 1; 416(1): 149-161.
There are two main lines of inquiry that we focus on in our laboratory. Our research aims to 1) define the molecular mechanisms that drive hematopoietic stem cells to develop into T cells, and 2) to understand how certain subsets of T cells are programmed for specialized functions in mucosal tissues such as the lungs and the female reproductive tract. We approach these questions through the lens of transcriptional regulation, with a focus on the E protein transcription factors HEBAlt and HEBCan.
T cell commitment can be defined as the point at which a developing cell loses the ability adopt any other fate. This process occurs in a specialized organ called the thymus. The earliest precursors to enter the thymus are not yet committed to the T cell lineage but also have the potential to become dendritic cells or natural killer cells. Upregulation of the T-lineage genes needed for commitment to the T-cell lineage and for exclusion of other lineage choices is induced in part by the interaction of the Notch1 receptor with the Delta-like ligands expressed on thymic stromal cells. One of the transcriptional regulators induced by Notch signaling is HEBAlt. We have shown that HEBAlt plays important roles in T cell development both in suppression of non-T lineages and in regulation of key T-lineage genes. We have also discovered that HEB factors play critical roles in the development of IL-17 producing T cells, which are concentrated in barrier tissues such as the skin, intestine, lung, and vagina. While IL-17 is needed for protection against bacteria and fungi, it is also heavily involved in the pathology of multiple autoimmune diseases. Understanding how HEB factors regulate T cell development and function will provide new avenues towards treating autoimmune conditions without a general suppression of immunity.
There are currently three main projects ongoing in the laboratory:
- Understanding the specific functions of HEBAlt and HEBCan in T cell development and function. We have generated new mouse models that express or lack different combinations of HEBAlt and HEBCan, and are using them to determine how they function in collaboration or opposition to each other during T cell development and in peripheral T cell function. These analyses include single cell RNA-seq, ChIC-seq, and testing of the immune response using mouse models of autoimmunity and disease.
- Defining the roles of HEB factors in human T cell development. Recent breakthroughs in technology have given us new tools to be able to study human T cell development in vitro. We are examining when HEBAlt is expressed in developing T cells derived from umbilical cord blood precursors or induced pluripotent stem cells, and assessing whether it plays similar roles in human and mouse T cell development.
- Examining the roles of HEBAlt and HEBCan in human T cell leukemia. HEB factors are important regulators of T cell growth control, which is severely dysregulated in leukemic T cells. We are studying the interactions between Notch signaling and HEB factors and how they affect human leukemic T cell growth and survival.