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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Prabhudas, Mercy R
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University of Michigan Ann Arbor
Anatomy/Cell Biology
Schools of Medicine
Ann Arbor
United States
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Hosoya, Tomonori; D'Oliveira Albanus, Ricardo; Hensley, John et al. (2018) Global dynamics of stage-specific transcription factor binding during thymocyte development. Sci Rep 8:5605
Ku, Chia-Jui; Sekiguchi, JoAnn M; Panwar, Bharat et al. (2017) GATA3 Abundance Is a Critical Determinant of T Cell Receptor ? Allelic Exclusion. Mol Cell Biol 37:
Ohmura, Sakie; Mizuno, Seiya; Oishi, Hisashi et al. (2016) Lineage-affiliated transcription factors bind the Gata3 Tce1 enhancer to mediate lineage-specific programs. J Clin Invest 126:865-78
Ku, Chia-Jui; Lim, Kim-Chew; Kalantry, Sundeep et al. (2015) A monoallelic-to-biallelic T-cell transcriptional switch regulates GATA3 abundance. Genes Dev 29:1930-41
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 146:157-165.e10
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
Lim, Kim-Chew; Hosoya, Tomonori; Brandt, William et al. (2012) Conditional Gata2 inactivation results in HSC loss and lymphatic mispatterning. J Clin Invest 122:3705-17