Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Sci Immunol. 2020 Jun 5;5(48). doi: 10.1126/sciimmunol.aba0570.
Oropharyngeal candidiasis (OPC; thrush) is an opportunistic infection caused by the commensal fungus Interleukin-17 (IL-17) and IL-22 are cytokines produced by type 17 lymphocytes. Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far less well delineated. We show that, despite having similar requirements for induction from type 17 cells, IL-22 and IL-17 function nonredundantly during OPC. We find that the IL-22 and IL-17 receptors are required in anatomically distinct locations within the oral mucosa; loss of IL-22RA1 or signal transducer and activator of transcription 3 (STAT3) in the oral basal epithelial layer (BEL) causes susceptibility to OPC, whereas IL-17RA is needed in the suprabasal epithelial layer (SEL). Transcriptional profiling of the tongue linked IL-22/STAT3 not only to oral epithelial cell proliferation and survival but also, unexpectedly, to driving an IL-17-specific gene signature. We show that IL-22 mediates regenerative signals on the BEL that replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17 and thus to mediate antifungal events. Consequently, IL-22 signaling in BEL "licenses" IL-17 signaling in the oral mucosa, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis.
口咽念珠菌病（OPC；鹅口疮）是一种机会性感染，由共生真菌引起。白细胞介素-17（IL-17）和 IL-22 是 17 型淋巴细胞产生的细胞因子。这两种细胞因子都介导抗真菌免疫，但激活的下游信号通路却截然不同。虽然现在已经了解了 IL-17 如何促进 OPC 中的免疫，但 IL-22 的活性却远未得到充分描绘。我们表明，尽管 17 型细胞诱导产生 IL-22 和 IL-17 的要求相似，但在 OPC 中，IL-22 和 IL-17 的功能并不冗余。我们发现，IL-22 和 IL-17 受体在口腔黏膜的解剖学上不同位置都有要求；在口腔基底上皮层（BEL）中缺失 IL-22RA1 或信号转导和转录激活因子 3（STAT3）会导致 OPC 易感性，而 IL-17RA 在口腔上皮层（SEL）中是必需的。对舌头的转录谱分析将 IL-22/STAT3 与口腔上皮细胞增殖和存活联系起来，但出乎意料的是，还与驱动特定于 IL-17 的基因特征有关。我们表明，IL-22 在 BEL 上介导再生信号，补充表达 IL-17RA 的 SEL，从而恢复口腔上皮对 IL-17 的反应能力，并介导抗真菌事件。因此，BEL 中的 IL-22 信号“授权”了口腔黏膜中的 IL-17 信号，揭示了 IL-22 和 IL-17 在口腔念珠菌病中的空间上不同但协作的活动。
