Acute IL-4 Governs Pathogenic T Cell Responses during Leishmania major Infection.
Acute IL-4 Governs Pathogenic T Cell Responses during Leishmania major Infection.
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DOI：
10.4049/immunohorizons.2000076
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发表时间：
2020-09-18
期刊：
影响因子：
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通讯作者：
Gurung P
中科院分区：
文献类型：
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作者：
Poudel B;Yorek MS;Mazgaeen L;Brown SA;Kanneganti TD;Gurung P
利什曼感染是一个全球性的健康问题，每年影响200多万人，全世界有3亿人处于危险之中。已充分确定，显性Th 1应答（IFN-γ，标志性Th 1细胞因子）提供抗性，而显性Th 2应答（IL-4，标志性Th 2细胞因子）在感染期间赋予易感性。鉴于IL-4在L.主要感染，我们使用IL-4中和抗体来研究由IL-4信号转导调节的细胞和分子事件。如前所述，IL-4在L.主要感染的BALB/c小鼠（利什曼原虫易感株）与对照L.主要感染BALB/c小鼠。尽管有这种保护，T细胞产生的IFN-γ却显著减少。IL-4的时间中和揭示了在感染的第一天内产生的急性IL-4不仅对于编程产生IL-4的Th 2 CD 4 + T细胞至关重要，而且对于促进由CD 8 + T细胞产生的IFN-γ至关重要。从机制上讲，IL-4信号传导增强了CD 4+和CD 8 + T细胞中抗CD 3诱导的Tbet和IFN-γ表达。考虑到IFN-γ产生性CD 8 + T细胞的致病作用，我们的数据表明IL-4不仅通过促进Th 2免疫应答而且通过促进致病性CD 8 + T细胞应答来促进皮肤利什曼病病理学。我们的研究为探讨IL-4在调节Th 1和Th 2应答中的未知作用开辟了新的研究基础。ImmunoHorizons，2020，4：546-560。
Leishmania spp. infection is a global health problem affecting more than 2 million people every year with 300 million at risk worldwide. It is well established that a dominant Th1 response (IFN-γ, a hallmark Th1 cytokine) provides resistance, whereas a dominant Th2 response (IL-4, a hallmark Th2 cytokine) confers susceptibility during infection. Given the important role of IL-4 during L. major infection, we used IL-4–neutralizing Abs to investigate the cellular and molecular events regulated by IL-4 signaling. As previously published, neutralization of IL-4 in L. major–infected BALB/c mice (a Leishmania susceptible strain) provided protection when compared with control L. major–infected BALB/c mice. Despite this protection, IFN-γ production by T cells was dramatically reduced. Temporal neutralization of IL-4 revealed that acute IL-4 produced within the first days of infection is critical for not only programming IL-4–producing Th2 CD4+ T cells, but for promoting IFN-γ produced by CD8+ T cells. Mechanistically, IL-4 signaling enhances anti-CD3–induced Tbet and IFN-γ expression in both CD4+ and CD8+ T cells. Given the pathogenic role of IFN-γ–producing CD8+ T cells, our data suggest that IL-4 promotes cutaneous leishmaniasis pathology by not only promoting Th2 immune responses but also pathogenic CD8+ T cell responses. Our studies open new research grounds to investigate the unsuspected role of IL-4 in regulating both Th1 and Th2 responses. ImmunoHorizons, 2020, 4: 546–560.