Impairment in the Expression and Activity of Fyn During Differentiation of Naive CD4+ T Cells into the Th2 Subset

Tamura, Toshiki; Igarashi, Osamu; Hino, Ayako; Yamane, Hidehiro; Aizawa, Shinichi; Kato, Takuma; Nariuchi, Hideo

doi:10.4049/jimmunol.167.4.1962

Cited by 35 publications

(36 citation statements)

References 38 publications

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“…Unc119 constitutively associates with Abl and inhibits its enzymatic activity. Abl/ Arg-double deficient T cells and Fyn-deficient T cells demonstrate selective impairment of IFN-g production (9,10). Abl kinases are critical for the activation of JNK in T cells (10).…”

Section: Discussionmentioning

confidence: 99%

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Uncoordinated 119 Preferentially Induces Th2 Differentiation and Promotes the Development of Asthma

Górska

Goplen²,

Qiang³

et al. 2010

The Journal of Immunology

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The Th2 bias is a hallmark of allergic diseases. In this study, we show that the Th1 versus Th2 balance and the development of allergic asthma are strongly affected by the signaling protein uncoordinated 119 (Unc119). The expression of this adaptor protein is significantly increased in Th2 cells. Unc119 activates the Src family and inhibits the Abl family of tyrosine kinases. The activated Src family kinase Lck stimulates the activity of Itk and the expression of the transcription factor JunB. As a result, Unc119 promotes IL-4 production. Through inhibition of Abl kinases, Unc119 dampens IFN-γ production. Using adoptive transfer of Unc119-knockdown CD4 T cells, we show a critical role for Unc119 in the development of eosinophilic inflammation of airways, mucus production, and bronchial hyperreactivity in a mouse model. Intriguingly, the expression of the Unc119 protein is enhanced in CD4 T cells from patients with asthma. We speculate that the heightened expression of Unc119 promotes Th2, inhibits Th1 differentiation, and contributes to the pathogenesis of asthma in humans.

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Section: Discussionmentioning

confidence: 99%

“…The Tec family includes Txk and Itk. Lck and Itk have been shown to favor Th2 development, whereas Fyn and Txk support the differentiation of Th1 cells (6)(7)(8)(9). A recent study indicates that tyrosine kinases of the Abl family, Abl and Arg, are critical for IFN-g production, but redundant for IL-4 synthesis in nonpolarized T cells (10).…”

mentioning

confidence: 99%

Uncoordinated 119 Preferentially Induces Th2 Differentiation and Promotes the Development of Asthma

Górska

Goplen²,

Qiang³

et al. 2010

The Journal of Immunology

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“…This decrease could enhance Th2 development because Fyn mediates inhibition of Th2 cytokine expression during Th0 development (37). However, treatment with the RXR agonist did not produce a consistent change in Fyn mRNA expression (Table I).…”

Section: Rxr Agonist Increases Th2 and Decreases Th1 Gene Expression mentioning

confidence: 99%

Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway

Stephensen

Rasooly

Jiang

et al. 2002

The Journal of Immunology

148

108

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Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses. To identify a potential mechanism(s) underlying this in vivo activity of vitamin A, we examined the effects of all-trans and 9-cis RA on development of Th1 and Th2 cell populations using in vitro stimulation of Ag-naive Th0 cells from the DO11.10 TCR-transgenic mouse. Treatment with 9-cis, but not with all-trans RA, at primary stimulation strongly enhanced Th2 development. IL-4-neutralizing Ab blocked this activity, but IL-12- and IFN-γ-neutralizing Ab did not. Because 9-cis RA regulates gene transcription via either RA receptors or retinoid X receptors (RXRs), we tested the Th2-enhancing activities of the RXR- and RA receptor-selective agonists AGN194204 and 4-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB). AGN194204 strongly enhanced Th2 development, whereas TTNPB did not. This RXR agonist also enhanced Th2 development when purified, naive Th0 cells (L-selectinhigh/CD4+) were stimulated with CD3 and CD28 Abs in the absence of APCs. During primary antigenic stimulation of naive Th0 cells from DO11.10 mice, AGN194204 increased IL-4 and IL-5 production, decreased IFN-γ production, increased mRNA in responding T cells for genes involved in Th2 development (IL-4, GATA-3, and c-maf), and decreased mRNA for genes involved in Th1 development (IFN-γ, T-bet, and IL-12R). These data show that stimulation of the RXR pathway enhances Th2 development, perhaps by affecting the relative expression of pertinent transcription factors, cytokines, and cytokine receptors.

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“…For example, the level of fyn expression in Th2 clones was one-third to one-fifth the level found in Th1 clones [12]. Furthermore, fyn-/-T cells differentiated into Th2 cells even in the absence of IL-4 [13]. These results suggest that fyn negatively regulates the differentiation of naive Th cells into Th2 cells.…”

Section: Introductionmentioning

confidence: 92%

Fyn regulates eosinophil infiltration into the conjunctiva by downregulating the Th2 response

Fukushima

Yamaguchi

Ozaki

et al. 2005

Graefe's Arch Clin Exp Ophthalmo

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Impairment in the Expression and Activity of Fyn During Differentiation of Naive CD4+ T Cells into the Th2 Subset

Cited by 35 publications

References 38 publications

Uncoordinated 119 Preferentially Induces Th2 Differentiation and Promotes the Development of Asthma

Uncoordinated 119 Preferentially Induces Th2 Differentiation and Promotes the Development of Asthma

Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway

Fyn regulates eosinophil infiltration into the conjunctiva by downregulating the Th2 response

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