Natural killer (NK) cells are innate lymphocytes that express germline encoded activating and inhibitory receptors. These cells have the capacity to rapidly kill virus- infected cells and cancer cells and modulate adaptive immune responses by regulating dendritic cells (DCs) and through production of pro-inflammatory cytokines. NK cells develop in the bone marrow and thymus from progenitors that also give rise to B and T lymphocytes, respectively. Despite the severe consequences of failed NK cell development (immune deficiency and malignancy), little is known about the mechanisms that control specification and commitment to this lymphoid lineage. While multiple transcription factors are required for NK cell development and function, most are required at a relatively late stage in the differentiation process and none of these factors are NK cell lineage specific. Therefore, the transcriptional networks that specify activation of the NK cell gene program from multipotent progenitors and maintain commitment to the NK cell lineage remain to be elucidated. We have focused on determining the functions of the E proteins and their antagonists, the inhibitors of differentiation (Id) proteins, since these transcription factors appear to function as molecular switches directing B or T versus NK cell differentiation, respectively.
In Aim 1 of this grant application we propose experiments to test the hypothesis that Id2 and Id3 cooperate to promote NK cell development in the bone marrow and thymus.
In Aim 2 we will determine the mechanisms by which E proteins antagonize NK cell development in different microenvironments. We will test the hypothesis that aberrant E protein activity results in activation of the B or T cell gene programs thereby causing ?lineage diversion? or ?lineage confusion? in NK lineage cells.
In Aim 3 we will characterize the transcription factors that promote NK cell lineage specific gene expression and determine whether these factors play a direct role in NK cell lineage specification. By identifying the essential components of the NK cell transcriptional program, and how these factors are influenced by the microenvironment, we will provide a basis for understanding how commitment to the NK cell lineage is achieved. Moreover, these studies will provide a foundation for future therapies aimed at altering the outcome of NK cell differentiation and for predicting the effects of therapeutic interventions on this developmental program. Project Narrative: Natural killer (NK) cells are lymphocytes that function in both adaptive and innate immune responses. The goal of our research is to determine the mechanisms controlling development NK cells from multipotent progenitors by identifying the essential transcription factors that promote lineage specification and commitment. Our studies will provide insight into how to how to manipulate this program to avoid disease and how therapeutic interventions will impact on NK cell development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA099978-10
Application #
8271306
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mccarthy, Susan A
Project Start
2003-04-01
Project End
2014-01-14
Budget Start
2012-06-01
Budget End
2014-01-14
Support Year
10
Fiscal Year
2012
Total Cost
$283,398
Indirect Cost
$93,696
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Verykokakis, Mihalis; Zook, Erin C; Kee, Barbara L (2014) ID'ing innate and innate-like lymphoid cells. Immunol Rev 261:177-97
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
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
Mandal, Malay; Powers, Sarah E; Maienschein-Cline, Mark et al. (2011) Epigenetic repression of the Igk locus by STAT5-mediated recruitment of the histone methyltransferase Ezh2. Nat Immunol 12:1212-20
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
Verykokakis, Mihalis; Boos, Markus D; Bendelac, Albert et al. (2010) Inhibitor of DNA binding 3 limits development of murine slam-associated adaptor protein-dependent "innate" gammadelta T cells. PLoS One 5:e9303
de Pooter, Renee F; Kee, Barbara L (2010) E proteins and the regulation of early lymphocyte development. Immunol Rev 238:93-109
Gao, Jie; Graves, Stephanie; Koch, Ute et al. (2009) Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 4:548-58
Dias, Sheila; Xu, Wei; McGregor, Stephanie et al. (2008) Transcriptional regulation of lymphocyte development. Curr Opin Genet Dev 18:441-8
Dias, Sheila; Mansson, Robert; Gurbuxani, Sandeep et al. (2008) E2A proteins promote development of lymphoid-primed multipotent progenitors. Immunity 29:217-27

Showing the most recent 10 out of 19 publications