title: Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells.
abstract: A proper balance between Th17 and T regulatory cells (Treg cells) is critical for generating protective immune responses while minimizing autoimmunity. We show that the Tec family kinase Itk (IL2-inducible T cell kinase), a component of T cell receptor (TCR) signaling pathways, influences this balance by regulating cross talk between TCR and cytokine signaling. Under both Th17 and Treg cell differentiation conditions, Itk(-/-) CD4(+) T cells develop higher percentages of functional FoxP3(+) cells, associated with increased sensitivity to IL-2. Itk(-/-) CD4(+) T cells also preferentially develop into Treg cells in vivo. We find that Itk-deficient T cells exhibit reduced TCR-induced phosphorylation of mammalian target of rapamycin (mTOR) targets, accompanied by downstream metabolic alterations. Surprisingly, Itk(-/-) cells also exhibit reduced IL-2-induced mTOR activation, despite increased STAT5 phosphorylation. We demonstrate that in wild-type CD4(+) T cells, TCR stimulation leads to a dose-dependent repression of Pten. However, at low TCR stimulation or in the absence of Itk, Pten is not effectively repressed, thereby uncoupling STAT5 phosphorylation and phosphoinositide-3-kinase (PI3K) pathways. Moreover, Itk-deficient CD4(+) T cells show impaired TCR-mediated induction of Myc and miR-19b, known repressors of Pten. Our results demonstrate that Itk helps orchestrate positive feedback loops integrating multiple T cell signaling pathways, suggesting Itk as a potential target for altering the balance between Th17 and Treg cells.
authors.affiliation: National Human Genome Research Institute, 2 National Institute of Allergy and Infectious Diseases, 3 National Institute of Arthritis and Musculoskeletal and Skin Diseases, and 4 National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Julio
authors.initials: J
authors.lastname: Gomez-Rodriguez
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Wohlfert
authors.forename: Robin
authors.initials: R
authors.lastname: Handon
authors.forename: Françoise
authors.initials: F
authors.lastname: Meylan
authors.forename: Julie Z
authors.initials: JZ
authors.lastname: Wu
authors.forename: Stacie M
authors.initials: SM
authors.lastname: Anderson
authors.forename: Martha R
authors.initials: MR
authors.lastname: Kirby
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Belkaid
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Schwartzberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D007111:Immunity, Cellular / Q000276:immunology*; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009841:Oligonucleotides / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D009841:Oligonucleotides; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse