Innate T cells, such as the invariant natural killer T cells (NKT cells), are extremely potent """"""""first responders"""""""" to infection. The aggressive nature of innate T cells has also made them attractive targets for immunotherapy - several clinical trials are in progress. Like conventional T cells, innate T cells develop in the thymus from hematopoietic precursor cells that commit to the T cell lineage in the thymus. Commitment to the NKT cell lineage does not occur until late in T cell development. We have recently discovered that the transcriptional regulator, PLZF, is the factor that controls the development of NKT cell effector functions. PLZF deficient NKT cells fail to acquire the effector functions ascribed to innate T cells and conventional T cells ectopically expressing PLZF spontaneously acquire effector/memory T cell phenotypes and functions. PLZF is >95% conserved at the amino acid level between mouse and man and, therefore, is nearly certainly functionally equivalent in people. Indeed, human NKT cells express high levels of PLZF. This application is focused on understanding the function of PLZF in NKT cells and the more general role this transcription factor plays in innate T cell development and function. We propose that PLZF is the single factor that controls the development and maintenance of effector functions in a variety of innate T cells;not only NKT cells. Our preliminary data show that the functions of all T lymphocytes are dramatically affected by the expression of PLZF. Therefore, studies to understand what T cells express PLZF, what effector functions are controlled by PLZF, how PLZF expression is initiated and the mechanism of PLZF regulation are critical for the full appreciation of the impact that this powerful transcription factor has on immunity. Our extensive knowledge of both conventional T cell development and NKT cell development in combination with a series of novel reagents and experimental systems puts in an excellent position to expand upon our knowledge of this critical transcription factor.

Public Health Relevance

Innate T cells, such as the invariant natural killer T cells (iNKT cells), are extremely potent """"""""first responders"""""""" to infection. The aggressive nature of innate T cells has also made them attractive targets for immunotherapy - several clinical trials are in progress. We have recently discovered that the transcriptional regulator, PLZF, is the single factor that controls the development of iNKT cell effector functions. In this proposal we will determine how PLZF expression helps to control the immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI083988-01A2
Application #
7993318
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$477,250
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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