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Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength.

ABSTRACT: TCR signal strength is critical for CD8⁺ T cell clonal expansion after Ag stimulation. Levels of the transcription factor IRF4 control the magnitude of this process through the induction of genes involved in proliferation and glycolytic metabolism. The signaling mechanism connecting graded TCR signaling to the generation of varying amounts of IRF4 is not well understood. In this study, we show that Ag potency regulates the kinetics but not the magnitude of NFAT1 activation in single mouse CD8⁺ T cells. Consequently, T cells that transduce weaker TCR signals exhibit a marked delay in Irf4 mRNA induction, resulting in decreased overall IRF4 expression in individual cells and increased heterogeneity within the clonal population. We further show that the activity of the tyrosine kinase ITK acts as a signaling catalyst that accelerates the rate of the cellular response to TCR stimulation, controlling the time to onset of Irf4 gene transcription. These findings provide insight into the function of ITK in TCR signal transduction that ultimately regulates IRF4 expression levels in response to variations in TCR signal strength.

SUBMITTER: Conley JM

PROVIDER: S-EPMC7343623 | biostudies-literature |

REPOSITORIES: biostudies-literature

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TCR signaling via Tec kinase ITK and interferon regulatory factor 4 (IRF4) regulates CD8+ T-cell differentiation.

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TCR signal strength controls thymic differentiation of discrete proinflammatory γδT cell subsetsistinct TCR signal strength requirements in the thymus

Project description:The murine thymus produces discrete γδ T cell subsets making either IFN-γ or IL-17, but the role of the TCR in this developmental process remains controversial. Here we generated a non-transgenic and polyclonal model of reduced TCR expression and signal strength selectively on γδ T cells. Mice haploinsufficient for both CD3γ and CD3δ (CD3DH) showed normal αβ thymocyte subsets but specific defects in γδ T cell development, namely impaired differentiation of IL-17-producing embryonic Vγ6+ (but not adult Vγ4+) γδ T cells and a marked depletion of IFN-γ-producing CD122+ NK1.1+ (Vγ1-biased) γδ T cells throughout life. As result, adult CD3DH mice showed defective peripheral IFN-γ responses and were resistant to experimental cerebral malaria. Thus, strong TCR signaling is required within specific developmental windows with distinct Vγ usage and differential cytokine production by effector γδ T cell subsets.

2016-03-29 | GSE71637 | GEO

T-cell signaling regulated by the Tec family kinase, Itk.

Project description:The Tec family tyrosine kinases regulate lymphocyte development, activation, and differentiation. In T cells, the predominant Tec kinase is Itk, which functions downstream of the T-cell receptor to regulate phospholipase C-gamma. This review highlights recent advances in our understanding of Itk kinase structure and enzymatic regulation, focusing on Itk protein domain interactions and mechanisms of substrate recognition. We also discuss the role of Itk in the development of conventional versus innate T-cell lineages, including both alphabeta and gammadelta T-cell subsets. Finally, we describe the complex role of Itk signaling in effector T-cell differentiation and the regulation of cytokine gene expression. Together, these data implicate Itk as an important modulator of T-cell signaling and function.

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TCR signal strength controls thymic differentiation of iNKT cell subsets

Project description:Three major phenotypically and functionally distinct invariant Natural Killer T (iNKT) cell subsets (iNKT1, iNKT17 and iNKT2), each with propensity to traffic to different tissues and to secrete different cytokines upon activation, have been defined. These fate assignments can be conferred upon iNKT cells during development in the thymus, but the cues that direct these decisions remain unclear. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets in the thymus, with high signaling strength necessary for iNKT2 and iNKT17 development. Alteration of TCR diversity and/or signaling dramatically diminished iNKT2 and iNKT17 cell subset development in a cell intrinsic manner. Decreased TCR signaling affected the persistence of Egr2 expression and the upregulation of PLZF both in vivo and in vitro. Genome-wide chromatin accessibility analysis revealed subset-specific activity of regulatory elements associated with unique signatures of transcription factor binding sites. NFAT and Egr binding motifs were found preferentially enriched in chromatin regulatory regions specifically accessible in iNKT2 cells that were lost in iNKT2 cells that had developed with reduced TCR signaling. Altogether, these data suggest a model of iNKT cell subset development where variable TCR signaling induces changes in chromatin accessibility at NFAT and Egr binding sites which exerts a determinative influence on the dynamic of gene enhancer accessibility that affects the developmental fate of iNKT cells.

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TCR signal strength controls thymic differentiation of iNKT cell subsets

2018-05-17 | GSE110327 | GEO

The Tec family kinase Itk exists as a folded monomer in vivo.

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Project description:Th9 cells produce interleukin (IL)-9, a cytokine implicated in allergic asthma and autoimmunity. Here we show that Itk, a mediator of T cell receptor signalling required for Th2 immune responses and the development of asthma, is a positive regulator of Th9 differentiation. In a model of allergic lung disease, Itk-deficient mice show reduced pulmonary inflammation and IL-9 production by T cells and innate lymphoid type 2 cells (ILC2), despite normal early induction of ILC2s. In vitro, Itk(-/-) CD4(+) T cells do not produce IL-9 and have reduced levels of IRF4 (Interferon Regulator Factor 4), a critical transcription factor for effector T cell function. Both IL-9 and IRF4 expression are rescued by either IL-2 or constitutively active STAT5, but not NFATc1. STAT5 binds the Irf4 promoter, demonstrating one mechanism by which IL-2 rescues weakly activated T cells. Itk inhibition also reduces IL-9 expression by human T cells, implicating ITK as a key regulator of Th9 induction.

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