Jak3 is a protein kinase required for signaling through ctyokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Previous studies have shown that mutations in Jak3 result in a severe combined immunodeficiency syndrome (SCID) in humans, indicating that Jak3 plays an absolutely essential role in the fuction of the immune system. In addition, pharmacological inhibitors of Jak3 are currently being developed for use as immunosuppressants. Nonetheless, the precise role of Jak3 in T cell activation, differentiation, and homeostasis is currently uncertain, as are the consequences of long-term inhibition of Jak3 activity. We have developed an animal model using Jak3-deficient mice that will allow us to address the role of Jak3- dependent cytokine signaling in normal cells and in intact animals. Our recent data, based on findings from gene expression profiling and cytokine analysis experiments, indicate that the CD4+ T cells present in Jak3-/- mice closely resemble regulatory T cells of the Treg-1 (Tr1) phenotype. These cells are non- proliferative in vitro, and secrete large amounts of Ifn-g, IL-10, and TGF-b following TCR stimulation, but no IL-2 or IL-4. In addition, they have high constitutive levels of the inhibitory surface receptor, PD-1. Preliminary data also suggest that these Jak3-/- T cells can suppress proliferative responses of wild type T cells in vitro. Our hypothesis is that Jak3-dependent cytokine signals are critical for the differentiation of activated T cells into functional, conventional effector T cells, and that in the absence of these signals, activated T cells differentiate into Tr1 regulatory T cells. We also hypothesize that the """"""""activation"""""""" of Jak3-/- CD4+ T cells results from the homeostatic proliferation of these cells in the lymphophenic environment of the Jak3-/- host. To test these hypotheses, we propose to determine whether Jak3 -/- CD4+ T cells function as regulatory T cells, and the role(s) of IL-10, TGF-b, and PD-1 in this function. Second, we will examine the differentiation pathway of na'ive Jak3-/- CD4+ T cells following antigen stimulation in vitro and in vivo, and following homeostatic expansion in a lymphopenic wild type host. Finally, we will determine the role of StatS as a downstream mediator of Jak-3 dependent cytokine signals in regulating effector T cell versus regulatory T cell differentiation pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046564-08
Application #
7343159
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2000-03-01
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
8
Fiscal Year
2008
Total Cost
$348,277
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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