Impaired NFATc Translocation and Failure of Th2 Development in Itk-Deficient CD4+ T Cells

Fowell, Deborah J.; Shinkai, Kanade; Liao, Xiang; Beebe, Amy M.; Coffman, Robert L.; Littman, Dan R.; Locksley, Richard M.

doi:10.1016/s1074-7613(00)80115-6

Cited by 291 publications

(310 citation statements)

References 70 publications

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“…The tyrosine kinase ITK has been reported to be involved in the activation of T cells leading to T H 2 cell differentiation in vitro and in T H 2 type responses to pathogens in vivo (35,37). Since allergic asthma has many hallmarks of a T H 2-type response in humans and in animal models, we tested whether ITK may be involved in the allergic inflammatory response in the lung to the model allergen OVA in a murine model of allergic asthma.…”

Section: Itk Null Mice Exhibit Reduced Lung Inflammation Following Almentioning

confidence: 99%

“…Triggering the TCR also results in increases in intracellular calcium, which can activate the protein phosphatase calcineurin and mediate other downstream effects (38). The influx of calcium in T cells is controlled by ITK and mice lacking ITK have reduced calcium increases upon stimulation (37,39). Indeed, the calcineurin inhibitors cyclosporin A and FK506 have been suggested as treatments for asthma patients (40).…”

mentioning

confidence: 99%

“…These mice also have reduced naive T cell function in IL-2 production and proliferation when stimulated via the TCR (32,36,39). In addition, T cells from mice lacking ITK either secrete no IL-4 or significantly less IL-4 than normal T cells, an event that seems to be dependent on the ITK-mediated calcium increase (35,37).…”

mentioning

confidence: 99%

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Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Mueller

August

2003

The Journal of Immunology

146

137

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Allergic asthma patients manifest airway inflammation and some show increases in eosinophils, TH2 cells, and cytokines, increased mucous production in the lung, and elevated serum IgE. This TH2-type response suggests a prominent role for TH2 cells and their cytokines in the pathology of this disease. The Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) has been shown to play a role in the differentiation and/or function of TH2-type cells, suggesting that ITK may represent a good target for the control of asthma. Using a murine model of allergic asthma, we show here that ITK is involved in the development of immunological symptoms seen in this model. We show that mice lacking ITK have drastically reduced lung inflammation, eosinophil infiltration, and mucous production following induction of allergic asthma. Notably, T cell influx into the lung was reduced in mice lacking ITK. T cells from ITK−/− mice also exhibited reduced proliferation and cytokine secretion, in particular IL-5 and IL-13, in response to challenge with the allergen OVA, despite elevated levels of total IgE and increased OVA-specific IgE responses. Our results suggest that the tyrosine kinase ITK preferentially regulates the secretion of the TH2 cytokines IL-5 and IL-13 and may be an attractive target for antiasthmatic drugs.

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Section: Itk Null Mice Exhibit Reduced Lung Inflammation Following Almentioning

confidence: 99%

mentioning

confidence: 99%

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Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Mueller

August

2003

The Journal of Immunology

146

137

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“…Naive, small, CD62L high , CD4 ϩ T cells were purified to Ͼ99% using flow cytometry (MoFlo MultiLaser; Cytomation, Fort Collins, CO) and labeled with CFSE (Molecular Probes, Eugene, OR) as described (23). Purified T cells were activated in vitro using 10 6 CD4 ϩ T with 5 ϫ 10 6 irradiated APCs prepared from TCR-C␣-deficient mice, and mAbs to TCR␤ (1 g/ ml) and CD28 (5 g/ml) with 50 U/ml recombinant human IL-2 as described (23); omission of IL-2 had no effect on any of the described phenotypes.…”

Section: T Cell Purification and Activationmentioning

confidence: 99%

“…Where indicated, T cells were activated in the presence of both anti-IL-4 and anti-IFN-␥, or with anti-IL-12 (10 g/ml; R&D Systems, Minneapolis, MN), CTLA-4/Ig (4 g/ml; Ancell, Bayport, ME), or IL-6 (10 ng/ml; R&D Systems). T cells activated in the absence of APC were stimulated using tissue culture plates precoated with anti-TCR␤ and anti-CD28 as described (23).…”

Section: T Cell Purification and Activationmentioning

confidence: 99%

Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint

Mohrs

Lacy

Locksley

2003

The Journal of Immunology

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Activation of naive Th lymphocytes by the TCR and the costimulatory molecule, CD28, is believed to provide competent signals for differentiation to effector cells. Such activated cells proliferated and expressed IL-2, but arrested in an immature state maintained by CTLA-4. Although unresponsive to restimulation by TCR/CD28 alone, restimulation with TCR/CD28 and either Stat4- or Stat6-mediated cytokine signals rescued cells to proliferate and differentiate to the appropriately matched canonical Th subsets. Addition of IL-4 at defined periods revealed that naive T cells were receptive to IL-4-mediated differentiation for up to 3 days after their initial priming. A Stat-dependent anergic checkpoint between clonal expansion and effector cell differentiation may defer the cytokine profile to be instructed at the site of infection, thus preventing the unregulated development of potentially damaging effector cells.

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TGF-β1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression

et al. 2000

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TGF‐β plays an important role in immune regulation in vivo and affects T cell differentiation in vitro. Here we describe how TGF‐β modulates Th2 development in vitro and investigate its mechanisms of action. TGF‐β down‐regulated Th2 development of naive CD4+ Mel‐14high T cells derived from the DO11.10 ovalbumin‐specific TCR‐transgenic mouse, and this was observed both in cultures driven with anti‐CD3 and anti‐CD28 and with splenic APC and antigen. TGF‐β down‐regulated GATA‐3 expression in developing Th2 and these cells showed a diminished IL‐4‐induced STAT6 activation. We found, however, that naive cells driven in Th2 conditions with TGF‐β did not show a significantly decreased STAT6 activation, suggesting that TGF‐β inhibits Th2 development via a STAT6‐independent mechanism.

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Impaired NFATc Translocation and Failure of Th2 Development in Itk-Deficient CD4+ T Cells

Cited by 291 publications

References 70 publications

Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK

Stat Signals Release Activated Naive Th Cells from an Anergic Checkpoint

TGF-β1 down-regulates Th2 development and results in decreased IL-4-induced STAT6 activation and GATA-3 expression

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