Goupil Mathieu, Cousineau-Côté Vincent, Aumont Francine, Sénéchal Serge, Gaboury Louis, Hanna Zaher, Jolicoeur Paul, de Repentigny Louis
Department of Microbiology, Infectious Diseases and Immunology, Faculty of Medicine, University of Montreal, C.P. 6128, succursale Centre-Ville, Montreal, Quebec, H3C 3J7, Canada.
Pathology and Cell Biology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
BMC Immunol. 2014 Oct 26;15:49. doi: 10.1186/s12865-014-0049-9.
The tissue-signaling cytokines IL-17 and IL-22 are critical to host defense against oral Candida albicans infection, by their induction of oral antimicrobial peptide expression and recruitment of neutrophils. Mucosal Th17 cells which produce these cytokines are preferentially depleted in HIV-infected patients. Here, we tested the hypothesis that defective IL-17- and IL-22-dependent host responses to C. albicans determine the phenotype of susceptibility to oropharyngeal candidiasis (OPC) in transgenic (Tg) mice expressing HIV-1.
Naïve CD4+ T-cells and the differentiated Th1, Th2, Th17, Th1Th17 and Treg lineages were all profoundly depleted in cervical lymph nodes (CLNs) of these Tg mice. However, naive CD4+ cells from Tg mice maintained the capacity to differentiate into these lineages in response to polarizing cytokines in vitro. Expression of Il17, Il22, S100a8 and Ccl20 was enhanced in oral mucosal tissue of non-Tg, but not of Tg mice, after oral infection with C. albicans. Treatment of infected Tg mice with the combination of IL-17 and IL-22, but not IL-17 or Il-22 alone, significantly reduced oral burdens of C. albicans and abundance of Candida hyphae in the epithelium of tongues of infected Tg mice, and restored the ability of the Tg mice to up-regulate expression of S100a8 and Ccl20 in response to C. albicans infection.
These findings demonstrate that defective IL-17- and IL-22-dependent induction of innate mucosal immunity to C. albicans is central to the phenotype of susceptibility to OPC in these HIV transgenic mice.
组织信号细胞因子白细胞介素-17（IL-17）和白细胞介素-22（IL-22）对于宿主抵御口腔白色念珠菌感染至关重要，它们可诱导口腔抗菌肽表达并募集中性粒细胞。产生这些细胞因子的黏膜辅助性T细胞17（Th17）在HIV感染患者中优先减少。在此，我们检验了以下假设：对白色念珠菌的IL-17和IL-22依赖性宿主反应缺陷决定了表达HIV-1的转基因（Tg）小鼠对口咽念珠菌病（OPC）的易感性表型。
在这些Tg小鼠的颈部淋巴结（CLN）中，幼稚CD4 + T细胞以及分化的Th1、Th2、Th17、Th1Th17和调节性T细胞（Treg）谱系均显著减少。然而，Tg小鼠的幼稚CD4 +细胞在体外对极化细胞因子作出反应时仍保持分化为这些谱系的能力。白色念珠菌口腔感染后，非Tg小鼠而非Tg小鼠的口腔黏膜组织中Il17、Il22、S100a8和Ccl20的表达增强。用IL-17和IL-22联合治疗感染的Tg小鼠，而非单独使用IL-17或Il-22，可显著降低感染的Tg小鼠口腔中白色念珠菌的负荷以及舌上皮中念珠菌菌丝的丰度，并恢复Tg小鼠在白色念珠菌感染后上调S100a8和Ccl20表达的能力。
这些发现表明，对白色念珠菌的IL-17和IL-22依赖性先天性黏膜免疫诱导缺陷是这些HIV转基因小鼠对OPC易感性表型的核心。
