title: IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology.
abstract: Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.forename: Thomas
authors.initials: T
authors.lastname: Calzascia
authors.forename: Jesse G
authors.initials: JG
authors.lastname: Toe
authors.forename: Simon P
authors.initials: SP
authors.lastname: Preston
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lin
authors.forename: Alisha R
authors.initials: AR
authors.lastname: Elford
authors.forename: Arda
authors.initials: A
authors.lastname: Shahinian
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Lang
authors.forename: Karl S
authors.initials: KS
authors.lastname: Lang
authors.forename: Michel
authors.initials: M
authors.lastname: Morre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Assouline
authors.forename: Katharina
authors.initials: K
authors.lastname: Lahl
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Sameh
authors.initials: S
authors.lastname: Basta
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology / Q000627:therapeutic use*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D051379:Mice; D061026:Programmed Cell Death 1 Receptor; D011994:Recombinant Proteins / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000943:Antigens, Differentiation; D051858:Forkhead Transcription Factors; D015850:Interleukin-6; D015851:Interleukin-7; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011994:Recombinant Proteins; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins