Intrahepatic innate lymphoid cells secrete IL-17A and IL-17F that are crucial for T cell priming in viral infection.

Intrahepatic cell-derived, early IL-17 is important for activating antigen-presenting cells in viral infection; however, the source and regulation of this IL-17 surge in the liver microenvironment are not well defined. Here, we present evidence for a significant expansion of IL-17A/F-producing cells in mouse liver within 24 h of adenovirus (Ad) infection. In addition to λδ T cells, a subset of IL-17A/F+ cells expressed no myeloid or lymphoid lineage markers. Instead, they expressed high levels of stem cell markers, IL-7 receptor and RORλt, consistent with the newly described innate lymphoid cells. Based on their unique surface markers and cytokine profiles, these cells were confirmed as group 3 innate lymphoid cells (ILC3s). In addition to Ad infection, ILC3s were also found in mouse liver within 24 h of LCMV infection. They contributed significantly to the establishment of the early cytokine milieu in virus-infected liver. Functional studies with mice deficient of IL-17 receptor, IL-17A, and IL-17F further revealed that IL-17 signaling was critical for priming T cell responses in viral hepatitis. IL-17A repressed IL-17F secretion in vitro and in vivo; IL-17F+ intrahepatic cells expanded more vigorously in IL-17A knockout animals, permitting efficient antigen-presentation and T cell function. However, IL-17F neither inhibited IL-17A in vitro, nor regulated its secretion in vivo. Together, this study has demonstrated the importance of a unique intrahepatic subpopulation and subsequent IL-17A/F regulation at initial stages of viral infection in the liver. These results have important implications for anti-cytokine biologic therapy and vaccine development.

肝内细胞衍生的早期白细胞介素 - 17（IL - 17）在病毒感染中对激活抗原呈递细胞很重要；然而，肝脏微环境中这种IL - 17激增的来源和调控尚未明确界定。在此，我们提供证据表明在腺病毒（Ad）感染24小时内小鼠肝脏中产生IL - 17A/F的细胞显著扩增。除了γδ T细胞外，一部分IL - 17A/F⁺细胞不表达髓系或淋巴系谱系标记。相反，它们高水平表达干细胞标记、IL - 7受体和RORγt，与新描述的固有淋巴细胞一致。基于它们独特的表面标记和细胞因子谱，这些细胞被确认为3型固有淋巴细胞（ILC3s）。除了Ad感染，在淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染24小时内小鼠肝脏中也发现了ILC3s。它们对病毒感染肝脏中早期细胞因子环境的建立有重要作用。对缺乏IL - 17受体、IL - 17A和IL - 17F的小鼠进行的功能研究进一步表明，IL - 17信号传导对病毒性肝炎中T细胞应答的启动至关重要。IL - 17A在体外和体内抑制IL - 17F的分泌；在IL - 17A敲除动物中，IL - 17F⁺肝内细胞更强烈地扩增，从而允许有效的抗原呈递和T细胞功能。然而，IL - 17F在体外既不抑制IL - 17A，在体内也不调控其分泌。总之，这项研究证明了在肝脏病毒感染初始阶段一种独特的肝内亚群以及随后的IL - 17A/F调控的重要性。这些结果对抗细胞因子生物治疗和疫苗开发具有重要意义。