In this grant we propose a number of experiments aimed at understanding in detail the role of the transcription factor GATA-3 during CD4/CD8 lineage commitment in the thymus. We have recently shown that GATA-3 is differentially expressed in immature thymocytes that develop into the CD4 lineage, and that by modifying GATA-3 activity in the thymus we can bias lineage commitment. We will now: Dissect the mechanisms that regulate TCR-induced GATA-3 upregulation in the thymus, using a gain-of function/loss-of-function genetic approach to identify the signal transduction pathways involved in this process in normal DP thymocytes. Use reaggregate fetal thymic organ culture (rFTOC), lentiviral transgenesis and different GATA-3 mutants to map the structural regions of GATA-3 required for its effect during CD4/CD8 lineage commitment. Analyze the interactions of GATA-3 with two transcription factors, Egr-2 and Lmo-4, that we have identified as preferentially expressed in CD4 lineage intermediates in a genome-wide screen. These studies should provide us with a better understanding of the mechanisms that control CD4/CD8 lineage commitment, and, more widely, will provide clues about the genetic networks that establish cell fate determination and developmental programs in the thymus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI059302-02
Application #
6984842
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Macchiarini, Francesca
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
2
Fiscal Year
2006
Total Cost
$334,183
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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Hu, Taishan; Gimferrer, Idoia; Alberola-Ila, José (2011) Control of early stages in invariant natural killer T-cell development. Immunology 134:1-7
Hu, Taishan; Gimferrer, Idoia; Simmons, Amie et al. (2011) The Ras/MAPK pathway is required for generation of iNKT cells. PLoS One 6:e19890
Gimferrer, Idoia; Hu, Taishan; Simmons, Amie et al. (2011) Regulation of GATA-3 expression during CD4 lineage differentiation. J Immunol 186:3892-8
Carreras, Esther; Turner, Sean; Frank, Mark Barton et al. (2010) Estrogen receptor signaling promotes dendritic cell differentiation by increasing expression of the transcription factor IRF4. Blood 115:238-46
Hu, Taishan; Simmons, Amie; Yuan, Joan et al. (2010) The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage. Nat Immunol 11:435-41
Lauritsen, Jens-Peter Holst; Kurella, Sridevi; Lee, Sang-Yun et al. (2008) Egr2 is required for Bcl-2 induction during positive selection. J Immunol 181:7778-85