B lymphocytes, the producers of antibodies, are an essential component of the adaptive immune response. These cells develop from multipotent progenitors through a process that is dependent on the coordinated activity of numerous transcriptional regulatory proteins. However, very little is known about the mechanisms by which these factors control the differentiation process and how their activities are regulated. Mice that lack the transcription factors encoded by the E2A or EBF genes have a profound B cell immune deficiency resulting from the failure to develop cells that are committed to differentiation through the B lymphocyte lineage. The E2A proteins, El2 and E47, are also required for proper T lymphocyte development and to suppress the development of T cell lymphoma. The mechanisms by which the E2A proteins activate B lineage specific gene expression and promote B lineage determination are currently not known (Aim 1). Our preliminary data indicate that EBF is one of the essential targets of E2A that promote B lineage determination. We propose to test the hypothesis that EBF is the major target of E2A required for B lineage commitment (Aim 2). The E2A proteins function at the apex of a transcriptional cascade that culminates in B lineage commitment; however, it is not known how E2A activity is regulated during this process. We hypothesize that altered expression of E2A antagonists, the Id proteins, in lineage-unrestricted progenitors restricts the fate of the developing cell by influencing E2A activity. This hypothesis will be tested using both in vitro and in vivo models of Id gene regulation (Aim3). These studies will lead to a greater understanding of the genetic basis for lineage determination and will provide insight into the essential requirements for proper lymphocyte development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA099978-04S1
Application #
7288039
Study Section
Immunobiology Study Section (IMB)
Program Officer
Ogunbiyi, Peter
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2006-08-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2006
Total Cost
$54,760
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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Verykokakis, Mihalis; Zook, Erin C; Kee, Barbara L (2014) ID'ing innate and innate-like lymphoid cells. Immunol Rev 261:177-97
Verykokakis, Mihalis; Krishnamoorthy, Veena; Iavarone, Antonio et al. (2013) Essential functions for ID proteins at multiple checkpoints in invariant NKT cell development. J Immunol 191:5973-83
Xu, Wei; Carr, Tiffany; Ramirez, Kevin et al. (2013) E2A transcription factors limit expression of Gata3 to facilitate T lymphocyte lineage commitment. Blood 121:1534-42
Pereira de Sousa, Ana; Berthault, Claire; Granato, Alessandra et al. (2012) Inhibitors of DNA binding proteins restrict T cell potential by repressing Notch1 expression in Flt3-negative common lymphoid progenitors. J Immunol 189:3822-30
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de Pooter, Renee F; Kee, Barbara L (2010) E proteins and the regulation of early lymphocyte development. Immunol Rev 238:93-109
Ramirez, Kevin; Kee, Barbara L (2010) Multiple hats for natural killers. Curr Opin Immunol 22:193-8
Verykokakis, Mihalis; Boos, Markus D; Bendelac, Albert et al. (2010) SAP protein-dependent natural killer T-like cells regulate the development of CD8(+) T cells with innate lymphocyte characteristics. Immunity 33:203-15

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