Scientist profiles A-F
Sunnybrook Health Sciences Centre
2075 Bayview Ave., Room M7 615
Administrative Assistant: Melisha Abeysena
Phone: 416-480-6100, ext. 85482
- B.Sc., 1989, biology, Eckerd College, U.S.
- PhD, 1994, biochemistry and molecular biology, University of South Florida, U.S.
Appointments and Affiliations:
- Senior scientist, Biological Sciences, Odette Cancer Research Program, Sunnybrook Research Institute
- Associate professor, department of immunology, University of Toronto
- Transcriptional regulation of T cell development
Our overarching goal is to understand how T cells develop from stem cells, at the molecular and cellular levels. During embryonic development, three germ layers are formed: endoderm, ectoderm and mesoderm. Mesodermal tissues give rise to hematopoietic stem cells, which can become any of the eight major blood cell types, including T cells. As these processes occur, new genes are expressed while others are shut down, as directed by proteins known as transcription factors. We are studying two related transcription factors, HEBAlt and HEBCan. HEBCan is broadly expressed, whereas HEBAlt appears to be highly regulated to early stages of T cell development. We have evidence that both HEBAlt and HEBCan are involved in directing hematopoietic stem cells to become T cells and that they can regulate the ability to produce cytokines, which convey important signals to immune cells during immune reactions.
We use embryonic stem cell differentiation and mouse models to study the HEB factors by disrupting or changing their functions using genome editing. Using human embryonic stem cells, we have found that HEB factors are important in the generation of mesoderm, the formation of hematopoietic stem cells and T cell development. In the mouse, we have found that HEBAlt promotes the development of T cells from hematopoietic stem cells in concert with other transcription factors such as Notch and Bcl11b. Moreover, HEB factors are essential for the genetic programming of a specific type of T cell called gamma delta T cells, which reside in mucosal tissues such as the lung, reproductive tract and intestines. Without HEB, these cells are unable to make IL-17. IL-17, while important for barrier immunity, is linked to many autoimmune diseases. Finding ways to control HEB activity may thus enable modulation of these conditions, including multiple sclerosis and psoriasis.
Our long-term goal is to understand how HEB factors work within the context of the gene regulatory networks that drive cell identity and function. Ultimately, it is in these interaction networks that new ways of controlling the generation of specific blood cell types will be found. In addition, our work is providing valuable insights into how to maximize immunity against infection while providing protection against autoimmunity. Our studies of human embryonic development have also provided a compelling rationale for further studies into genetic defects and disorders that could result from misregulation of HEB factors.
- Anderson MK. Changing course by lymphocyte lineage redirection. Nat Immunol. 2013 Mar;14(3):199–201.
- Moore AJ, Sarmiento J, Mohtashami M, Braunstein M, Zuniga-Pflucker JC, Anderson MK. Transcriptional priming for intrathymic precursors for dendritic cell development. Development. 2012 Jan;139(2):373–84.
- Braunstein M, Anderson MK. HEB-deficient T-cell precursors lose T-cell potential and adopt an alternative pathway of differentiation. Mol Cell Bio. 2011 Mar;31(5):971–82.
- Braunstein M, Anderson MK. Developmental progression of fetal HEB-/- precursors to the pre-T cell stage is restored by HEBAlt. Eur J Immunol. 2010 Nov;40(11):3173–82.
- Wang D, Claus CL, Rajkumar P, Braunstein M, Moore AJ, Sigvardsson M, Anderson MK. Context-dependent regulation of hematopoietic lineage choice by HEBAlt. J Immunol. 2010 Oct1;185(7):4109–17.
Related News and Stories:
- Scientists score high with operating funds: CIHR invests in eight researchers in its latest competition (May 30, 2012)
- T cell fundamentals: Sunnybrook biologist’s research is laying the groundwork for future trials in immunity to cancer and other diseases (June 18, 2007)