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

• Published in: The Journal of immunology (1950) 2014-04, Vol.192 (7), p.3289-3300
• Main Authors: Jie, Zuliang, Liang, Yuejin, Hou, Lifei, Dong, Chen, Iwakura, Yoichiro, Soong, Lynn, Cong, Yingzi, Sun, Jiaren
• Format: Article
• Language: English
• Subjects: Adenoviridae - immunology; Adenoviridae - physiology; Animals; Cells, Cultured; Chemokine CXCL10 - genetics; Chemokine CXCL10 - immunology; Chemokine CXCL10 - metabolism; Chemokine CXCL9 - genetics; Chemokine CXCL9 - immunology; Chemokine CXCL9 - metabolism; Female; Flow Cytometry; Host-Pathogen Interactions - immunology; Interferon-gamma - genetics; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukin-17 - metabolism; Liver - immunology; Liver - metabolism; Liver - virology; Lymphocytes - classification; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytic choriomeningitis virus - immunology; Lymphocytic choriomeningitis virus - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Antigen, T-Cell, gamma-delta - immunology; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - immunology; Receptors, Interleukin-17 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Virus Diseases - immunology; Virus Diseases - virology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1303281

Intrahepatic cell-derived, early IL-17 is important for activating APCs in viral infection; however, the source and regulation of this IL-17 surge in the liver microenvironment are not well defined. In this article, we present evidence for a significant expansion of IL-17A/F-producing cells in mouse liver within 24 h of adenovirus infection. In addition to γδ 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-7R and RORγt, consistent with the newly described innate lymphoid cells (ILCs). Based on their unique surface markers and cytokine profiles, these cells were confirmed as group 3 ILCs. In addition to adenovirus infection, group 3 ILCs were also found in mouse liver within 24 h of lymphocytic choriomeningitis virus infection. They contributed significantly to the establishment of the early cytokine milieu in virus-infected liver. Functional studies with mice deficient of IL-17R, 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 Ag 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 anticytokine biologic therapy and vaccine development.