The common γ-chain cytokine IL-7 promotes immunopathogenesis during fungal asthma

• Published in: Mucosal immunology Vol. 11; no. 5; pp. 1352 - 1362
• Main Authors: Reeder, Kristen M., Dunaway, Chad W., Blackburn, Jonathan P., Yu, Zhihong, Matalon, Sadis, Hastie, Annette T., Ampleford, Elizabeth J., Meyers, Deborah A., Steele, Chad
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.09.2018; Nature Publishing Group US; Elsevier Limited
• Subjects: Adult; Allergology; Antibodies; Asthma; Asthma - immunology; Asthma - microbiology; Biomedical and Life Sciences; Biomedicine; Bronchoalveolar Lavage Fluid - immunology; Bronchoalveolar Lavage Fluid - microbiology; CCL17 protein; CCL22 protein; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - microbiology; Chemokines; Chemokines - immunology; Cytokines; Cytokines - immunology; Female; Fungi; Fungi - immunology; Gastroenterology; Humans; IL-1β; Immunology; Immunopathogenesis; Inflammation; Interleukin 13; Interleukin 22; Interleukin 4; Interleukin 5; Interleukin 7; Interleukin-7 - immunology; Leukocytes (eosinophilic); Lung - immunology; Lung - microbiology; Lymphocytes T; Male; Mycoses - immunology; Pilot Projects; Respiratory function
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/s41385-018-0028-1

Asthmatics sensitized to fungi are reported to have more severe asthma, yet the immunopathogenic pathways contributing to this severity have not been identified. In a pilot assessment of human asthmatics, those subjects sensitized to fungi demonstrated elevated levels of the common γ-chain cytokine IL-7 in lung lavage fluid, which negatively correlated with the lung function measurement PC20. Subsequently, we show that IL-7 administration during experimental fungal asthma worsened lung function and increased the levels of type 2 cytokines (IL-4, IL-5, IL-13), proallergic chemokines (CCL17, CCL22) and proinflammatory cytokines (IL-1α, IL-1β). Intriguingly, IL-7 administration also increased IL-22, which we have previously reported to drive immunopathogenic responses in experimental fungal asthma. Employing IL22CreR26ReYFP reporter mice, we identified γδ T cells, iNKT cells, CD4 T cells and ILC3s as sources of IL-22 during fungal asthma; however, only iNKT cells were significantly increased after IL-7 administration. IL-7-induced immunopathogenesis required both type 2 and IL-22 responses. Blockade of IL-7Rα in vivo resulted in attenuated IL-22 production, lower CCL22 levels, decreased iNKT cell, CD4 T-cell and eosinophil recruitment, yet paradoxically increased dynamic lung resistance. Collectively, these results suggest a complex role for IL-7 signaling in allergic fungal asthma.