title: Allele-sensitive mutant, Itkas, reveals that Itk kinase activity is required for Th1, Th2, Th17, and iNKT-cell cytokine production.
abstract: Itk(-/-) mice exhibit defects in the activation, development, and function of CD4(+) and CD8(+) T cells and iNKT cells. These and other defects in these mice make it difficult to uncouple the developmental versus functional requirement of Itk signaling. Here, we report an allele-sensitive mutant of Itk (Itkas) whose catalytic activity can be selectively inhibited by analogs of the PP1 kinase inhibitor. We show that Itkas behaves like WT Itk in the absence of the inhibitor and can rescue the development of Itk(-/-) T cells in mice. Using mice carrying Itkas, we show using its inhibitor that Itk activity is required not only for Th2, Th17, and iNKT-cell cytokine production, but also surprisingly, for Th1 cytokine production. This work has important implications for understanding the role of Itk signaling in the development versus function of iNKT cells, Th1, Th2, and Th17 cells.
authors.affiliation: Center for Infection and Pathobiology, Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Kannan
authors.affiliation: Center for Infection and Pathobiology, Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
authors.forename: YongChan
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Center for Infection and Pathobiology, Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Center for Infection and Pathobiology, Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
authors.forename: Weishan
authors.initials: W
authors.lastname: Huang
authors.affiliation: Keck School of Medicine of University of Southern California, Los Angeles, CA, USA.
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Jeong
authors.affiliation: Center for Infection and Pathobiology, Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ohnigian
authors.affiliation: Center for Infection and Pathobiology, Department of Microbiology and Immunology, Cornell University, Ithaca, NY, USA.
authors.forename: Avery
authors.initials: A
authors.lastname: August
mesh_terms: D000483:Alleles; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D016207:Cytokines; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase
keywords: Allele-sensitive; Cytokines; Itk; Kinase inhibitor; Tec kinase; iNKT-cell