T lymphocyte maturation in the thymus is maintained by the continuous influx of hematopoietic progenitors that are ultimately derived from bone marrow hematopoietic stem cells. Transcription factor GATA-3 is a critical regulator of T cell and thymic natural killer (NK) cell development, and has been shown to be vital for multiple stages of T cell development. Our recent studies revealed that GATA-3 is required for the development of the earliest T cell progenitor (ETP), the most immature T cell in the thymus. By way of contrast, we also demonstrated that GATA-3 is not required prior to the ETP stage for the development of fetal liver or adult bone marrow pre-thymic progenitors that bear T cell potential. This vital demonstration was functionally difficult to address because no T cells can be generated from GATA3-null progenitors, but we were able to definitively demonstrate this requirement using a novel Gata3-eGFP hypomorphic allele. Thus GATA-3 is required at the earliest stage of T lymphopoiesis as well as at intermediate and late stages of thymocyte development and for CD4+ T cell Th2 differentiation in the periphery. Although the transcriptional hierarchy mediated by GATA-3 (the transcription factor) and through Gata3 (the gene) is beginning to be characterized in peripheral T cells, its hierarchical activity in the T cell transcriptional regulaory network in the thymus remains largely unknown. We recently identified a Gata3 T and NK cell-specific enhancer located 280 kbp 3'to the Gata3 structural gene. Here we propose to characterize the GATA-3-centric transcriptional network that controls T cell development from the most immature hematopoietic progenitor stages through to the mature Th2 stage. Contributing to our understanding of GATA-3 regulation in early thymopoiesis may be critical for eventually deciphering the etiology and progression of T cell leukemias and lymphomas, since aberrant GATA- 3 expression has been implicated as a causal agent in a subset of these diseases.

Public Health Relevance

T lymphocytes are an indispensable component of the vertebrate adaptive immune response, and defects or aberrant development during T lymphopoiesis can result in compromised immunological competence or leukemia. The interplay of multiple transcription factors regulates proper T lymphocyte development, and GATA-3 plays a critical role in their maturation and activation. Successful execution of this research program will fundamentally contribute to our understanding of the transcriptional network(s) that controls T cell development from hematopoietic stem cells, which in turn should contribute in the future to the development of new therapeutic approaches to hematopoietic diseases, including leukemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI094642-02
Application #
8416960
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Prabhudas, Mercy R
Project Start
2012-02-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$364,168
Indirect Cost
$129,168
Name
University of Michigan Ann Arbor
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Yamazaki, Hiromi; Suzuki, Mikiko; Otsuki, Akihito et al. (2014) A remote GATA2 hematopoietic enhancer drives leukemogenesis in inv(3)(q21;q26) by activating EVI1 expression. Cancer Cell 25:415-27
Udager, Aaron M; Prakash, Ajay; Saenz, David A et al. (2014) Proper development of the outer longitudinal smooth muscle of the mouse pylorus requires Nkx2-5 and Gata3. Gastroenterology 146:157-65.e10