Abstract

Natural killer (NK) cells play a critical role in immunity to some viruses and they protect against hematopoietic malignancy but their uncontrolled activity can lead to pathology due to excess cytokine production and inflammation. One goal of our research is to identify the transcriptional networks that control the development and function of NK cells. Previous studies from our laboratory showed that the ETS1 transcription factor is an important regulator of NK cell development and function and limits activation of NK cells in response to endogenous cytokine. In this grant, mice with a conditional allele of Ets1 will be used to delete Ets1 from mature NK cells providing a model system that will allow us to test the hypothesis that ETS1 has distinct but essential requirements during development, maturation, and activation of NK cells. An understanding of the molecular mechanisms controlling development and activation of NK cells will provide a foundation on which to control their function in situations of immune deficiency or hyper-activity when control of NK cell function would be beneficial, such as for immunotherapy.

Public Health Relevance

Natural killer (NK) cells are non-B and non-T lymphocytes that are essential for clearance of certain viruses and protection from hematopoietic malignancy. ETS1 is required for proper development of NK cells and the few NK cells that persist in the absence of ETS1 are hyper-responsive to cytokine stimulation. Here will determine whether ETS1 is required in mature NK cells for their effector maturation and function or whether the altered selection of ETS1-deficient NK cells underlies they altered phenotype and hypersensitivity.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI115388-02
Application #
8995189
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2015-01-15
Project End
2016-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
2
Fiscal Year
2016
Total Cost
$232,940
Indirect Cost
$82,940

  Institution

Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637

  Publications

Gabrielli, Sara; Sun, Mengxi; Bell, April et al. (2017) Murine thymic NK cells are distinct from ILC1s and have unique transcription factor requirements. Eur J Immunol 47:800-805
Verykokakis, Mihalis; Kee, Barbara L (2017) Applying the TOR(C)QUE in iNKT cells: A new twist in an old tale. Eur J Immunol 47:454-457
Zook, Erin C; Ramirez, Kevin; Guo, Xiaohuan et al. (2016) The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2. J Exp Med 213:687-96