Inducible Costimulator Expression Regulates the Magnitude of Th2-Mediated Airway Inflammation by Regulating the Number of Th2 Cells
Inducible Costimulator Expression Regulates the Magnitude of Th2-Mediated Airway Inflammation by Regulating the Number of Th2 Cells
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DOI：
10.1371/journal.pone.0007525
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发表时间：
2009-11-04
期刊：
影响因子：
3.7
通讯作者：
Sperling, Anne I.
中科院分区：
文献类型：
--
作者：
Clay, Bryan S.;Shilling, Rebecca A.;Sperling, Anne I.
背景：诱导共刺激剂（ICOS）是Th2淋巴细胞功能的重要调节因子，是过敏症和哮喘的潜在免疫治疗靶点。人类ICOS 5'启动子的SNP与创始人群中特异性和血清IgE的增加以及外周血单核细胞ICOS表面表达和Th2细胞因子产生的增加有关。然而，目前尚不清楚ICOS表达的增加是导致疾病进展还是疾病病理的结果。方法/主要发现：我们建立了一个小鼠模型，其中ICOS表面表达水平是遗传预先决定的，以验证我们的假设，即ICOS表达的遗传调控控制了体内Th2反应的严重程度。在Th2气道炎症模型中使用ICOS（+/+）和ICOS（+/-）小鼠，我们发现ICOS（+/-）小鼠的T细胞体内ICOS表达减少，Th2介导的炎症减少。虽然T细胞的激活状态没有差异，但从炎症高峰期的ICOS（+/-）小鼠的肺和引流淋巴结分离的T细胞在体外刺激时产生的Th2细胞因子较少。利用IL-4转录表达GFP的4get小鼠，我们确定了ICOS中Th2细胞因子的减少（+/-）是由于Th2细胞百分比的减少，而不是它们产生IL-4的能力的缺陷。结论：这些数据表明，在小鼠和人类中，ICOS表面表达水平可能通过影响Th2分化来调节体内Th2反应的大小。
Background: Inducible Costimulator (ICOS) is an important regulator of Th2 lymphocyte function and a potential immunotherapeutic target for allergy and asthma. A SNP in the ICOS 5' promoter in humans is associated with increased atopy and serum IgE in a founder population and increased ICOS surface expression and Th2 cytokine production from peripheral blood mononuclear cells. However, it is unknown if increased ICOS expression contributes to disease progression or is a result of disease pathology.Methodology/Principal Findings: We developed a mouse model in which ICOS surface expression levels are genetically predetermined to test our hypothesis that genetic regulation of ICOS expression controls the severity of Th2 responses in vivo. Using ICOS(+/+) and ICOS(+/-) mice in a Th2 model of airway inflammation, we found that T cells from the ICOS(+/-) mice had reduced ICOS expression and decreased Th2-mediated inflammation in vivo. Although the activation status of the T cells did not differ, T cells isolated from the lungs and draining lymph nodes of ICOS(+/-) mice at the peak of inflammation produced less Th2 cytokines upon stimulation ex vivo. Using 4get mice, which express GFP upon IL-4 transcription, we determined that the decreased Th2 cytokines in ICOS(+/-) is due to reduced percentage of Th2 cells and not a defect in their ability to produce IL-4.Conclusion: These data suggest that in both mice and humans, the level of ICOS surface expression regulates the magnitude of the in vivo Th2 response, perhaps by influencing Th2 differentiation.