Production of IL-17A at Innate Immune Phase Leads to Decreased Th1 Immune Response and Attenuated Host Defense against Infection with Cryptococcus deneoformans
Production of IL-17A at Innate Immune Phase Leads to Decreased Th1 Immune Response and Attenuated Host Defense against Infection with Cryptococcus deneoformans
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DOI：
10.4049/jimmunol.1901238
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发表时间：
2020-06
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通讯作者：
Ko Sato;Hideki Yamamoto;Toshiki Nomura;J. Kasamatsu;T. Miyasaka;D. Tanno;Ikumi Matsumoto;Takafumi Kagesawa;Anna Miyahara;Tong-Kai Zong;Akiho Oniyama;K. Kawamura;Rin Yokoyama;Yuki Kitai;Shigenari Ishizuka;E. Kanno;H. Tanno;Hiromi Suda;Masanobu Morita;Masayuki Yamamoto;Y. Iwakura;K. Ishii;K. Kawakami
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作者：
Ko Sato;Hideki Yamamoto;Toshiki Nomura;J. Kasamatsu;T. Miyasaka;D. Tanno;Ikumi Matsumoto;Takafumi Kagesawa;Anna Miyahara;Tong-Kai Zong;Akiho Oniyama;K. Kawamura;Rin Yokoyama;Yuki Kitai;Shigenari Ishizuka;E. Kanno;H. Tanno;Hiromi Suda;Masanobu Morita;Masayuki Yamamoto;Y. Iwakura;K. Ishii;K. Kawakami
隐球菌感染后γδT细胞产生IL-17A。IL-17A调节th1介导的对隐球菌感染的保护。制备了高表达隐球菌Ag特异性TCR的Tg小鼠。IL-17A是多种先天免疫细胞和Th17细胞产生的促炎细胞因子，参与清除细胞外生长的微生物，但该细胞因子在宿主防御细胞内生长的微生物中的作用尚不清楚。隐球菌是一种机会性的细胞内生长真菌病原体，经常引起免疫反应受损的患者致命的脑膜脑炎。在本研究中，我们分析了IL-17A在宿主防御棘球蚴感染中的作用。IL-17A在感染肺部的先天免疫期由γδT细胞快速产生。在IL-17A基因被破坏的小鼠中，与野生型小鼠相比，感染小鼠肺部对这种真菌病原体的清除和Th1细胞介导的宿主免疫反应明显加快。同样，在IL-17A基因破坏的小鼠中，这种真菌的杀伤和诱导NO合成酶和TNF-α的产生显著增强。此外，il - 17a处理显著抑制NK和NKT细胞中真菌病原体的消除、Th1应答以及IL-12Rβ2和IFN-γ的表达。il - 17a可显著抑制巨齿弓形虫刺激的骨髓源树突状细胞IL-12p40和TNF-α的产生。此外，il - 17a在重组甘露糖蛋白98刺激后，在高表达甘露糖蛋白98（一种隐球菌Ag） TCR的转基因小鼠脾细胞中减弱Th1细胞分化。这些数据表明，IL-17A可能通过抑制Th1反应参与了局部宿主防御C. deeoformans感染的负向调控。
Key Points γδT cells produce IL-17A after cryptococcal infection. IL-17A regulates Th1-mediated protection against cryptococcal infection. Tg mice highly expressing TCR specific for cryptococcal Ag were generated. Visual Abstract IL-17A is a proinflammatory cytokine produced by many types of innate immune cells and Th17 cells and is involved in the elimination of extracellularly growing microorganisms, yet the role of this cytokine in the host defense against intracellularly growing microorganisms is not well known. Cryptococcus deneoformans is an opportunistic intracellular growth fungal pathogen that frequently causes fatal meningoencephalitis in patients with impaired immune responses. In the current study, we analyzed the role of IL-17A in the host defense against C. deneoformans infection. IL-17A was quickly produced by γδT cells at an innate immune phase in infected lungs. In IL-17A gene–disrupted mice, clearance of this fungal pathogen and the host immune response mediated by Th1 cells were significantly accelerated in infected lungs compared with wild-type mice. Similarly, killing of this fungus and production of inducible NO synthase and TNF-α were significantly enhanced in IL-17A gene–disrupted mice. In addition, elimination of this fungal pathogen, Th1 response, and expression of IL-12Rβ2 and IFN-γ in NK and NKT cells were significantly suppressed by treatment with rIL-17A. The production of IL-12p40 and TNF-α from bone marrow–derived dendritic cells stimulated with C. deneoformans was significantly suppressed by rIL-17A. In addition, rIL-17A attenuated Th1 cell differentiation in splenocytes from transgenic mice highly expressing TCR for mannoprotein 98, a cryptococcal Ag, upon stimulation with recombinant mannoprotein 98. These data suggest that IL-17A may be involved in the negative regulation of the local host defense against C. deneoformans infection through suppression of the Th1 response.