T cell development and activation are dependent on multiple independent signaling pathways. These include signals through T cell antigen receptors (TCRs), co-receptors, co-stimulatory receptors, cytokine receptors, adhesion molecules, and others. As tyrosine kinases are known to play a critical role in receptor proximal signaling events, we set out to identify novel tyrosine kinases expressed in T cells. This effort led to the cloning of Jak3, which was shown to be critical for signaling through gammac-containing cytokine receptors, including the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. To examine the role of Jak3 during lymphocyte development and activation, we generated Jak3-deficient mice, and have shown that T cell maturation and function are grossly aberrant in these mice. The importance of Jak3 in the immune system is also highlighted by the identification of human severe combined immunodeficiency patients whose disease is caused by mutations in the Jak3 gene. We propose to use the Jak3-deficient mice as a model system to investigate the precise role of Jak3 in the immune system. First, we will test the hypothesis that Jak3 plays a critical role in the development and/or survival of T cell progenitors in the thymus, fetal liver, or bone marrow. We will also examine the role of Jak3 in mature peripheral T cells, and test the idea that Jak3 is necessary for long-term T cell survival, responsiveness to antigenic stimulation, and activation-induced cell death. Finally, we will use a gene-targeting """"""""knock-in"""""""" strategy to perform structure/function analysis of Jak3 in vivo, allowing us to assess the activity of specific Jak3 mutants in primary cells. As tyrosine kinases have been implicated in numerous human immunodeficiency diseases and cancers, and are involved in decisions leading to proliferation versus differentiation in many cell lineages, these experiments will provide information relevant to an understanding of oncogenesis, autoimmunity, as well as genetic immunodeficiencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046564-02
Application #
6362431
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Hackett, Charles J
Project Start
2000-03-01
Project End
2005-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
2
Fiscal Year
2001
Total Cost
$257,882
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Chang, John T; Ciocca, Maria L; Kinjyo, Ichiko et al. (2011) Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34:492-504
Andreotti, Amy H; Schwartzberg, Pamela L; Joseph, Raji E et al. (2010) T-cell signaling regulated by the Tec family kinase, Itk. Cold Spring Harb Perspect Biol 2:a002287
Shi, Min; Lin, Tsung H; Appell, Kenneth C et al. (2009) Cell cycle progression following naive T cell activation is independent of Jak3/common gamma-chain cytokine signals. J Immunol 183:4493-501
Prince, Amanda L; Yin, Catherine C; Enos, Megan E et al. (2009) The Tec kinases Itk and Rlk regulate conventional versus innate T-cell development. Immunol Rev 228:115-31
Shi, Min; Lin, Tsung H; Appell, Kenneth C et al. (2008) Janus-kinase-3-dependent signals induce chromatin remodeling at the Ifng locus during T helper 1 cell differentiation. Immunity 28:763-73
Kosaka, Yoko; Felices, Martin; Berg, Leslie J (2006) Itk and Th2 responses: action but no reaction. Trends Immunol 27:453-60
Mayack, Shane R; Berg, Leslie J (2006) Cutting edge: an alternative pathway of CD4+ T cell differentiation is induced following activation in the absence of gamma-chain-dependent cytokine signals. J Immunol 176:2059-63
Berg, L J; Kang, J (2001) Molecular determinants of TCR expression and selection. Curr Opin Immunol 13:232-41
Gozalo-Sanmillan, S; McNally, J M; Lin, M Y et al. (2001) Cutting edge: two distinct mechanisms lead to impaired T cell homeostasis in Janus kinase 3- and CTLA-4-deficient mice. J Immunol 166:727-30
Baird, A M; Lucas, J A; Berg, L J (2000) A profound deficiency in thymic progenitor cells in mice lacking Jak3. J Immunol 165:3680-8