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author:("Sahu, nishita")
1.  Differential expression of IL-17A and IL-17F is coupled to TCR signaling via Itk-mediated regulation of NFATc1 
Immunity  2009;31(4):587-597.
Th17 cells play major roles in autoimmunity and bacterial infections, yet how T cell receptor (TCR) signaling affects Th17 differentiation is relatively unknown. We demonstrate that CD4+ T cells deficient in Itk, a tyrosine kinase required for full TCR-induced activation of PLC-γ, exhibit decreased IL-17A expression, yet relatively normal expression of RORγT, RORα and IL-17F. IL-17A expression was rescued by pharmacologically-induced Ca2+ influx or expression of activated NFATc1. Conversely, decreased TCR stimulation or FK506 treatment preferentially reduced expression of IL-17A. The promoter of IL-17A but not IL-17F has conserved NFAT binding sites that bind NFATc1 in WT, but not Itk-deficient cells, even though both promoters exhibit epigenetic modifications consistent with open chromatin. Finally, defective IL-17A expression and differential regulation of IL-17A and IL-17F were observed in vivo in Itk−/− mice in an allergic asthma model. Our results suggest that Itk specifically couples TCR signaling strength to IL-17A expression through NFATc1.
doi:10.1016/j.immuni.2009.07.009
PMCID: PMC2767186  PMID: 19818650
2.  Differential sensitivity to Itk kinase signals for T helper 2 cytokine production and chemokine mediated migration* 
Allergic asthma is dependent on chemokine mediated Th2 cell migration and Th2 cytokine secretion into the lungs. The tyrosine kinase Itk regulates the production of Th2 cytokines as well as migration in response to chemokine gradients. Mice lacking Itk are resistant to developing allergic asthma, however, the role of kinase activity of Itk in the development of this disease is unclear. In addition, whether distinct Itk derived signals lead to T cell migration and secretion of Th2 cytokines is also unknown. Using transgenic mice specifically lacking Itk kinase activity, we show that active kinase signaling is required for control of Th2 responses and development of allergic asthma. Moreover, dominant suppression of Itk kinase activity led to normal Th2 responses, but significantly reduced chemokine mediated migration, resulting in prevention of allergic asthma. These observations indicate that signals required for Th2 responses and migration are differentially sensitive to Itk kinase activity. Manipulation of Itk’s kinase activity can thus provide a new strategy to treat allergic asthma by differentially affecting migration of T cells into the lungs, leaving Th2 responses intact.
PMCID: PMC2913463  PMID: 18322190
3.  Modeling Susceptibility versus Resistance in Allergic Airway Disease Reveals Regulation by Tec Kinase Itk 
PLoS ONE  2010;5(6):e11348.
Murine models of allergic asthma have been used to understand the mechanisms of development and pathology in this disease. In addition, knockout mice have contributed significantly to our understanding of the roles of specific molecules and cytokines in these models. However, results can vary significantly depending on the mouse strain used in the model, and in particularly in understanding the effect of specific knockouts. For example, it can be equivocal as to whether specific gene knockouts affect the susceptibility of the mice to developing the disease, or lead to resistance. Here we used a house dust mite model of allergic airway inflammation to examine the response of two strains of mice (C57BL/6 and BALB/c) which differ in their responses in allergic airway inflammation. We demonstrate an algorithm that can facilitate the understanding of the behavior of these models with regards to susceptibility (to allergic airway inflammation) (Saai) or resistance (Raai) in this model. We verify that both C57BL/6 and BALB/c develop disease, but BALB/c mice have higher Saai for development. We then use this approach to show that the absence of the Tec family kinase Itk, which regulates the production of Th2 cytokines, leads to Raai in the C57BL/6 background, but decreases Saai on the BALB/c background. We suggest that the use of such approaches could clarify the behavior of various knockout mice in modeling allergic asthma.
doi:10.1371/journal.pone.0011348
PMCID: PMC2893210  PMID: 20596543
4.  Selective expression rather than specific function of Txk and Itk regulate TH1 and TH2 responses§ 
Itk and Txk/Rlk are Tec family kinases expressed in T cells. Itk is expressed in both TH1 and TH2 cells. By contrast, Txk is preferentially expressed in TH1 cells. Although Itk is required for TH2 responses in vivo and Txk is suggested to regulate IFNγ expression and TH1 responses, it remains unclear whether these kinases have distinct roles in TH cell differentiation/function. We demonstrate here that Txk null CD4+ T cells are capable of producing both TH1 and TH2 cytokines similar to those produced by WT CD4+ T cells. To further examine whether Itk and Txk play distinct roles in TH cell differentiation and function we examined Itk-null mice carrying a transgene that expresses Txk at levels similar to the expression of Itk in TH2 cells. Using two TH2 model systems: allergic asthma and Schistosome egg-induced lung granulomas, we found that the Txk transgene rescued TH2 cytokine production and all TH2 symptoms without notable enhancement of IFNγ expression. These results suggest that Txk is not a specific regulator of TH1 responses. Importantly, they suggest that Itk and Txk exert their effects on TH cell differentiation/function at the level of expression.
PMCID: PMC2849304  PMID: 18941202
5.  ITK Inhibitors in Inflammation and Immune-mediated Disorders 
Interleukin-2-inducible T cell kinase (ITK) is a non-receptor tyrosine kinase expressed in T cells, NKT cells and mast cells which plays a crucial role in regulating the T cell receptor (TCR), CD28, CD2, chemokine receptor CXCR4 and FcεR mediated signaling pathways. In T cells, ITK is an important mediator for actin reorganization, activation of PLCγ, mobilization of calcium, and activation of the NFAT transcription factor. ITK plays an important role in the secretion of IL-2, but more critically, also has a pivotal role in the secretion of Th2 cytokines, IL-4, IL-5 and IL-13. As such, ITK has been shown to regulate the development of effective Th2 response during allergic asthma as well as infections against parasitic worms. This ability of ITK to regulate Th2 responses, along with it's pattern of expression, has led to the proposal that it would represent an excellent target for Th2 mediated inflammation. We discuss here the possibilities and pitfalls of targeting ITK for inflammatory disorders.
PMCID: PMC2770952  PMID: 19689375
6.  Memory phenotype CD8+ T-cells with innate function selectively develop in the absence of active Itk 
European journal of immunology  2007;37(10):2892-2899.
Summary
T cells with a memory like phenotype and possessing innate immune function have been previously identified as CD8+CD44hi cells. These cells rapidly secrete IFNγ upon stimulation with IL-12/IL-18 and are involved in innate responses to infection with Listeria monocytogenes. The signals regulating these cells are unclear. The Tec kinase Itk regulates T cell activation and we report here that a majority of the CD8+ T cells in Itk null mice have a phenotype of CD44hi similar to memory like innate T cells. These cells are observed in mice carrying an Itk mutant lacking the kinase domain, indicating that active Tec kinase signaling suppresses their presence. These cells carry preformed message for and are able to rapidly produce IFNγ upon stimulation in vitro with IL-12/IL-18, and endow Itk null mice the ability to effectively respond to infection with L. monocytogenes or exposure to LPS by secretion of IFNγ. Transfer of these cells rescues the ability of IFNγ null mice to reduce bacterial burden following L. monocytogenes infection indicating that these cells are functional CD8+CD44hi T cells previously detected in vivo. These results indicate that active signals from Tec kinases regulate the development of memory like CD8+ T cells with innate function.
doi:10.1002/eji.200737311
PMCID: PMC2770953  PMID: 17724684
Listeria monocytogenes; Itk; IFNγ; IL-12
7.  Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma 
The Journal of Experimental Medicine  2008;205(6):1285-1292.
Eosinophils have been implicated as playing a major role in allergic airway responses. However, the importance of these cells to the development of this disease has remained ambiguous despite many studies, partly because of lack of appropriate model systems. In this study, using transgenic murine models, we more clearly delineate a role for eosinophils in asthma. We report that, in contrast to results obtained on a BALB/c background, eosinophil-deficient C57BL/6 ΔdblGATA mice (eosinophil-null mice via the ΔDblGATA1 mutation) have reduced airway hyperresponsiveness, and cytokine production of interleukin (IL)-4, -5, and -13 in ovalbumin-induced allergic airway inflammation. This was caused by reduced T cell recruitment into the lung, as these mouse lungs had reduced expression of CCL7/MCP-3, CC11/eotaxin-1, and CCL24/eotaxin-2. Transferring eosinophils into these eosinophil-deficient mice and, more importantly, delivery of CCL11/eotaxin-1 into the lung during the development of this disease rescued lung T cell infiltration and airway inflammation when delivered together with allergen. These studies indicate that on the C57BL/6 background, eosinophils are integral to the development of airway allergic responses by modulating chemokine and/or cytokine production in the lung, leading to T cell recruitment.
doi:10.1084/jem.20071836
PMCID: PMC2413027  PMID: 18490489
8.  Differential Regulation of Cytokine Production by CD1d-Restricted NKT Cells in Response to Superantigen Staphylococcal Enterotoxin B Exposure  
Infection and Immunity  2006;74(1):282-288.
NKT cells are a heterogeneous population characterized by the ability to rapidly produce cytokines, such as interleukin 2 (IL-2), IL-4, and gamma interferon (IFN-γ) in response to infections by viruses, bacteria, and parasites. The bacterial superantigen staphylococcal enterotoxin B (SEB) interacts with T cells bearing the Vβ3, -7, or -8 T-cell receptors, inducing their expansion and cytokine secretion, leading to death in some cases due to cytokine poisoning. The majority of NKT cells bear the Vβ7 or -8 T-cell receptor, suggesting that they may play a role in regulating this response. Using mice lacking NKT cells (CD1d−/− and Jα18−/− mice), we set out to identify the role of these cells in T-cell expansion, cytokine secretion, and toxicity induced by exposure to SEB. We find that Vβ8+ CD4+ T-cell populations similarly expand in wild-type (WT) and NKT cell-null mice and that NKT cells did not regulate the secretion of IL-2. By contrast, these cells positively regulated the secretion of IL-4 and IFN-γ production and negatively regulated the secretion of tumor necrosis factor alpha (TNF-α). However, this negative regulation of TNF-α secretion by NKT cells provides only a minor protective effect on SEB-mediated shock in WT mice compared to mice lacking NKT cells. These data suggest that NKT cells may regulate the nature of the cytokine response to exposure to the superantigen SEB and may act as regulatory T cells during exposure to this superantigen.
doi:10.1128/IAI.74.1.282-288.2006
PMCID: PMC1346674  PMID: 16368982

Results 1-8 (8)