title: Attenuation of immune-mediated influenza pneumonia by targeting the inducible co-stimulator (ICOS) molecule on T cells.
abstract: Inducible Co-stimulator (ICOS) plays a critical role in mediating T cell differentiation and function and is considered a key player in balancing T effector and T regulatory (Treg) cell responses. Here we show that activation of the ICOS signalling pathway during acute influenza A virus (IAV) infection by application of an agonistic ICOS antibody reduced the frequency of CD8+ T cells in the respiratory tract of IAV infected animals and delayed pathogen elimination. In line with this, immune-mediated influenza pneumonia was significantly ameliorated in mice that received ICOS agonist as indicated by significantly reduced alveolar infiltrations and bronchointerstitial pneumonia, while at the same time virus-related pathology remained unaffected. Importantly, ICOS agonist treatment resulted in expansion of CD4+Foxp3+ Tregs in IAV infected mice, which was associated with elevated levels of the immunosuppressive cytokine IL-10 in the alveolar space. Together, our findings suggest a prominent role of ICOS signaling during acute IAV infection by increasing the Treg/CD8+ T cell ratio with beneficial outcome on immune-mediated pneumonia and underline the suitability of ICOS as potential therapeutic target for immune intervention in those infectious conditions characterized by strong immunopathology rather than virus-mediated cytopathic effects.
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Priya
authors.initials: P
authors.lastname: Sakthivel
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Infection Immunology Group, Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Gereke
authors.affiliation: Department of Veterinary Medicine, Institute of Veterinary Pathology, Free University, Berlin, Germany.
authors.forename: Angele
authors.initials: A
authors.lastname: Breithaupt
authors.affiliation: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, "A. Avogadro" University of Eastern Piedmont, Novara, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gigliotti
authors.affiliation: Department of Veterinary Medicine, Institute of Veterinary Pathology, Free University, Berlin, Germany.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: Department of Health Sciences and Interdisciplinary Research Center of Autoimmune Diseases, "A. Avogadro" University of Eastern Piedmont, Novara, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.affiliation: Immune Regulation Group, Helmholtz Centre for Infection Research, Braunschweig, Germany; Infection Immunology Group, Institute of Medical Microbiology, Infection Control and Prevention, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Dunja
authors.initials: D
authors.lastname: Bruder
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein / Q000819:agonists / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000821:virology; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009976:Orthomyxoviridae Infections / Q000150:complications*; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism
chemical_list: D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10