This is a competitive renewal of a previously funded application from an established investigator. T cell development and activation are dependent on multiple independent receptor signaling pathways. Since tyrosine kinases are known to play a critical role in receptor proximal signaling events, Dr. Berg previously set out to identify novel tyrosine kinases expressed in T cells. These efforts led to the cloning of Itk, a member of the Tec family of tyrosine kinases expressed only in T cells and NK cells. Btk, a close relative of Itk expressed in B cells and mast cells, has been shown to be the gene defective in human and mouse immunodeficiencies (X-linked agammaglobulinemia and XID, respectively). To examine the role of Itk in T cell signaling, Itk-deficient mice were generated and characterized. T cells from these mice are defective in TCR-induced calcium mobilization and cytokine production. A profound defect in positive selection in the thymus was also found. Using T cells from the Itk-deficient mice and retroviral gene transfer techniques, Dr. Berg proposes to define the protein domains and phosphorylation sites of Itk that are necessary for its role in TCR-induced calcium mobilization and cytokine production. She will characterize the biochemical defects in the Itk-deficient T cells, focusing on the transcription factors involved in IL-2 gene induction and the role of Itk in PLCgamma1 activation, and on CD28 signaling. Finally, she will address the role of Itk in T cell development by crossing the Itk-deficient mice to three different TCR transgenic lines, and then assess positive and negative selection in these mice. Together, these studies will provide important information on the role of Itk in both T cell development and T cell activation. As tyrosine kinases have been implicated in numerous human immunodeficiency diseases and cancers, and are involved in decisions leading to the proliferation versus differentiation in many cell lineages, these experiments will provide information relevant to an understanding of oncogenesis, autoimmunity, as well as genetic immunodeficiences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI037584-10
Application #
6607183
Study Section
Allergy and Immunology Study Section (ALY)
Program Officer
Macchiarini, Francesca
Project Start
1995-09-30
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
10
Fiscal Year
2003
Total Cost
$286,256
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
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
Min, Lie; Wu, Wenfang; Joseph, Raji E et al. (2010) Disrupting the intermolecular self-association of Itk enhances T cell signaling. J Immunol 184:4228-35
Sacristán, Catarina; Schattgen, Stefan A; Berg, Leslie J et al. (2009) Characterization of a novel interaction between transcription factor TFII-I and the inducible tyrosine kinase in T cells. Eur J Immunol 39:2584-95
Felices, Martin; Yin, Catherine C; Kosaka, Yoko et al. (2009) Tec kinase Itk in gammadeltaT cells is pivotal for controlling IgE production in vivo. Proc Natl Acad Sci U S A 106:8308-13
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
Felices, Martin; Berg, Leslie J (2008) The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival. J Immunol 180:3007-18
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
Lucas, Julie A; Felices, Martin; Evans, John W et al. (2007) Subtle defects in pre-TCR signaling in the absence of the Tec kinase Itk. J Immunol 179:7561-7

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