Yin-Yang 1 regulates effector cytokine gene expression and T(H)2 immune responses - PubMed (original) (raw)
Yin-Yang 1 regulates effector cytokine gene expression and T(H)2 immune responses
Jia Guo et al. J Allergy Clin Immunol. 2008 Jul.
Abstract
Background: The transcription factor Yin-Yang 1 (YY-1) binds to the promoter regions of several T-cell cytokine genes, but the expression and contribution of this factor to cytokine gene expression and T-cell activation in vivo is not clear.
Objective: We sought to better define the role of YY-1 in T-cell gene regulation and allergic immune responses.
Methods: We studied cytokine gene expression in T lymphocytes isolated from wild-type mice and heterozygous littermates bearing 1 targeted yy-1 allele (yy-1(+/-) mice). T cells were stimulated with anti-T-cell receptor (anti-TCR) plus CD28 antibodies or with peptide antigen plus antigen-presenting cells by using newly generated yy-1(+/-) TCR transgenic mice. We also studied ovalbumin-driven allergic immune responses in a mouse model of asthma and YY-1 expression in lung tissue from human asthmatic subjects.
Results: CD4(+) T cells from yy-1(+/-) mice secreted significantly less IL-4 and IFN-gamma compared with wild-type littermates after TCR-dependent activation, whereas IL-2 production was not significantly affected. Both airway inflammation and recall splenocyte IL-4 production were inhibited in yy-1(+/-) mice, as was antigen-driven T-cell proliferation. YY-1 expression was higher in airway biopsy specimens from asthmatic compared with control subjects.
Conclusion: These data indicate that YY-1 regulates T-cell cytokine gene expression and allergic immune responses in a gene dose-dependent manner.
Conflict of interest statement
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
Figures
FIG 1.
Effector cytokine secretion, YY-1 protein expression, and promoter occupancy are reduced in CD4+ T cells from yy-1+/− mice. CD4+ T cells were purified from WT and yy-1+/− heterozygous (HET) spleen cells and stimulated with anti-CD3/CD28 antibodies as indicated, followed by analysis of cytokine secretion by means of ELISA (A-C) or ChIP assay and PCR primers spanning the proximal IL-4 promoter (D). Results are the means ± SEMs of 4 to 5 mice per genotype analyzed in duplicate (Fig 1, A-C) or from 1 experiment representative of 3 (Fig 1, D).
FIG 2.
Antigen-driven CD4+ T-cell cytokine secretion is attenuated by partial yy-1 deficiency. Spleen CD4+ T cells were purified from WT or yy-1+/− (heterozygous) OTII.2 TCR transgenic mice and incubated with WT APCs and OVA323–339 peptide for 48 hours (see the Methods section). After 48 hours, supernatants were harvested, and cytokine secretion was analyzed by means of ELISA for IL-4 (A and C), IL-2 (B and D), and IFN-γ (E). Data in Fig 2, A and B, are from 1 experiment run in triplicate (representative of 3), whereas data in Fig 2, C through E, are the means ± SEMs of 4 mice per genotype. *P < .05 and **P < .01 for differences between genotypes.
FIG 3.
Airway inflammation and allergen-driven cytokine production are attenuated in yy-1+/− mice in a mouse model of asthma. WT and yy-1+/− (HET) mice were sensitized and challenged with OVA as indicated (see the Methods section), followed 48 hours later by analysis of lung lavage fluids by means of cytospin for eosinophils (A) and lymphocytes (B). Splenocytes were incubated with or without OVA (20 μg/mL) for 48 hours, and recall IL-4 expression was measured by means of ELISA (C) or RT-PCR compared with GATA-3 and GAPDH (D). Data are the means ± SEMs of 15 (Fig 3, A and B) or 20 (Fig 3, C) mice per genotype.
FIG 4.
YY-1 expression is increased in the airways in asthmatic subjects. Endobronchial biopsy specimens were obtained from healthy and asthmatic subjects and analyzed by using immunohistochemistry for expression of YY-1+ and CD3+ cells (see the Methods section). A and B show representative staining of YY-1 and CD3, respectively, from a subject with asthma. C shows the mean ± SEMs of 6 healthy and 12 asthmatic subjects, respectively.
FIG 5.
Partial YY-1 deficiency inhibits T-cell proliferation. Proliferation of spleen CD4+ T cells from WT and heterozygous (HET) mice was analyzed by monitoring CFSE dilution by means of immunofluorescence and flow cytometry. A shows representative data from 1 experiment, and B is the average ± SEMs of 3 experiments using antigen-stimulated TCR transgenic T cells from WT (red) and yy-1+/− (HET; blue) mice studied after 72 hours. *P < .05.
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