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 #
5R01AI083988-04
Application #
8278688
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
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$386,100
Indirect Cost
$138,600
Name
University of Medicine & Dentistry of NJ
Department
Pediatrics
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Monzon-Casanova, Elisa; Paletta, Daniel; Starick, Lisa et al. (2013) Direct identification of rat iNKT cells reveals remarkable similarities to human iNKT cells and a profound deficiency in LEW rats. Eur J Immunol 43:404-15
Thapa, Puspa; Das, Joy; McWilliams, Douglas et al. (2013) The transcriptional repressor NKAP is required for the development of iNKT cells. Nat Commun 4:1582
Alonzo, Eric S; Sant'Angelo, Derek B (2011) Development of PLZF-expressing innate T cells. Curr Opin Immunol 23:220-7
Beaulieu, Aimee M; Sant'Angelo, Derek B (2011) The BTB-ZF family of transcription factors: key regulators of lineage commitment and effector function development in the immune system. J Immunol 187:2841-7
Eidson, Maggie; Wahlstrom, Justin; Beaulieu, Aimee M et al. (2011) Altered development of NKT cells, ýýýý T cells, CD8 T cells and NK cells in a PLZF deficient patient. PLoS One 6:e24441