title: Interleukin-21 receptor signalling is important for innate immune protection against HSV-2 infections.
abstract: Interleukin (IL) -21 is produced by Natural Killer T (NKT) cells and CD4(+) T cells and is produced in response to virus infections, where IL-21 has been shown to be essential in adaptive immune responses. Cells from the innate immune system such as Natural Killer (NK) cells and macrophages are also important in immune protection against virus. These cells express the IL-21 receptor (IL-21R) and respond to IL-21 with increased cytotoxicity and cytokine production. Currently, however it is not known whether IL-21 plays a significant role in innate immune responses to virus infections. The purpose of this study was to investigate the role of IL-21 and IL-21R in the innate immune response to a virus infection. We used C57BL/6 wild type (WT) and IL-21R knock out (KO) mice in a murine vaginal Herpes Simplex Virus type 2 (HSV-2) infection model to show that IL-21 - IL-21R signalling is indeed important in innate immune responses against HSV-2. We found that the IL-21R was expressed in the vaginal epithelium in uninfected (u.i) WT mice, and expression increased early after HSV-2 infection. IL-21R KO mice exhibited increased vaginal viral titers on day 2 and 3 post infection (p.i.) and subsequently developed significantly higher disease scores and a lower survival rate compared to WT mice. In addition, WT mice infected with HSV-2 receiving intra-vaginal pre-treatment with murine recombinant IL-21 (mIL-21) had decreased vaginal viral titers on day 2 p.i., significantly lower disease scores, and a higher survival rate compared to infected untreated WT controls. Collectively our data demonstrate the novel finding that the IL-21R plays a critical role in regulating innate immune responses against HSV-2 infection.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Sine K
authors.initials: SK
authors.lastname: Kratholm
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Marie B
authors.initials: MB
authors.lastname: Iversen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Line
authors.initials: L
authors.lastname: Reinert
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Jensen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hokland
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Andersen
authors.affiliation: Immunology and Autoimmunity, Pfizer Inc. Cambridge, Massachusetts, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rankin
authors.affiliation: Immunology and Autoimmunity, Pfizer Inc. Cambridge, Massachusetts, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Young
authors.affiliation: The Water and Salt Research Centre, Institute of Anatomy, Aarhus University, Aarhus, Denmark.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Frische
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Søren R
authors.initials: SR
authors.lastname: Paludan
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Christian K
authors.initials: CK
authors.lastname: Holm
mesh_terms: D000818:Animals; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D018258:Herpesvirus 2, Human / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism*; D014621:Vagina / Q000378:metabolism / Q000821:virology; D019562:Viral Load
chemical_list: D053655:Receptors, Interleukin-21