Ya-Ting Chuang1, Krystle Leung2, Ya-Jen Chang3, Rosemarie H DeKruyff4, Paul B Savage5, Richard Cruse6, Christophe Benoit6, Dirk Elewaut7, Nicole Baumgarth8, Dale T Umetsu9. 1. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. 2. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass. 3. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. 4. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Department of Medicine, Stanford University, Stanford, Calif. 5. Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah. 6. Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Mass. 7. Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium; Unit for Molecular Immunology and Inflammation, VIB Inflammation Research Center, Ghent University, Ghent, Belgium. 8. Department of Pathology, Microbiology &Immunology, School of Veterinary Medicine, University of California, Davis, Calif. 9. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: dale.umetsu@gmail.com.
Abstract
BACKGROUND: Infection of suckling mice with influenza virus expands a CD4-CD8- double-negative (DN) natural killer T (NKT) cell subpopulation that protects the mice as adults against allergen-induced airway hyperreactivity (AHR). However, this NKT cell subset has not been characterized, and the underlying mechanisms of protection remain unknown. OBJECTIVE: We characterized this specific NKT cell subpopulation that developed during influenza infection in neonatal mice and that suppressed the subsequent development of AHR. METHODS: A cell-surface marker was identified by comparing the mRNA expression profile of wild-type CD4+ NKT cells with that of suppressive Vα14 DN NKT cells. The marker-enriched NKT cell subset was then analyzed for its cytokine profile and its suppressive in vitro and in vivo abilities. RESULTS: We showed that DN NKT cells with high CD38 expression produced IFN-γ, but not IL-17, IL-4, or IL-13, and inhibited development of AHR through contact-dependent suppression of helper CD4 T-cell proliferation. The NKT subset expanded in the lungs of neonatal mice after infection with influenza and also after treatment of neonatal mice with Nu-α-GalCer, which effectively increased DN CD38hi NKT cell numbers. CONCLUSION: These results suggest that early/neonatal exposure to infection or antigen challenge affects subsequent lung immunity by altering the cellular composition of cells in the lung and that some subsets of NKT cells suppress AHR. These results provide a possible mechanism by which prior infections can protect against the development of allergic asthma and might be further explored as a protective measure for young children.
BACKGROUND:Infection of suckling mice with influenza virus expands a CD4-CD8- double-negative (DN) natural killer T (NKT) cell subpopulation that protects the mice as adults against allergen-induced airway hyperreactivity (AHR). However, this NKT cell subset has not been characterized, and the underlying mechanisms of protection remain unknown. OBJECTIVE: We characterized this specific NKT cell subpopulation that developed during influenza infection in neonatal mice and that suppressed the subsequent development of AHR. METHODS: A cell-surface marker was identified by comparing the mRNA expression profile of wild-type CD4+ NKT cells with that of suppressive Vα14 DN NKT cells. The marker-enriched NKT cell subset was then analyzed for its cytokine profile and its suppressive in vitro and in vivo abilities. RESULTS: We showed that DN NKT cells with high CD38 expression produced IFN-γ, but not IL-17, IL-4, or IL-13, and inhibited development of AHR through contact-dependent suppression of helper CD4 T-cell proliferation. The NKT subset expanded in the lungs of neonatal mice after infection with influenza and also after treatment of neonatal mice with Nu-α-GalCer, which effectively increased DN CD38hi NKT cell numbers. CONCLUSION: These results suggest that early/neonatal exposure to infection or antigen challenge affects subsequent lung immunity by altering the cellular composition of cells in the lung and that some subsets of NKT cells suppress AHR. These results provide a possible mechanism by which prior infections can protect against the development of allergic asthma and might be further explored as a protective measure for young children.
Authors: Nelson M LaMarche; Harry Kane; Ayano C Kohlgruber; Han Dong; Lydia Lynch; Michael B Brenner Journal: Cell Metab Date: 2020-06-08 Impact factor: 27.287
Authors: Andrew D Prigge; Ruihua Ma; Bria M Coates; Benjamin D Singer; Karen M Ridge Journal: Am J Respir Cell Mol Biol Date: 2020-10 Impact factor: 6.914