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本帖最后由 freshnail 于 2011-2-4 01:11 编辑
http://www.cell.com/abstract/S0092-8674(11)00012-2
Cell, 03 February 2011
Copyright 2011 Elsevier Inc. All rights reserved.
10.1016/j.cell.2011.01.011
Authors
Marc Pellegrini, Thomas Calzascia, Jesse G. Toe, Simon P. Preston, Amy E. Lin, Alisha R. Elford, Arda Shahinian, Philipp A. Lang, Karl S. Lang, Michel Morre, Brigitte Assouline, Katharina Lahl, Tim Sparwasser, Thomas F. Tedder, Ji-hye Paik, Ronald A. DePinho, Sameh Basta, Pamela S. Ohashi, Tak W. MakSee AffiliationsHint: Rollover Authors and Affiliations The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia Department of Medical Biology, University of Melbourne, Melbourne 3050, Australia Departments of Medical Biophysics and Immunology, Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2C1, Canada Cytheris Inc., 92130 Issy les Moulineaux, France Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA Institute for Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str.7, 30625 Hannover, Germany Department of Immunology, Duke University Medical Center, Durham, NC 27708, USA Belfer Institute for Applied Cancer Science, Department of Medical Oncology, Department of Medicine and Department of Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Department of Microbiology and Immunology, Queen's University, Kingston, ON K7L 396, Canada Corresponding author These authors contributed equally to this work These authors contributed equally to this work
Highlights
•Socs3 is upregulated in T cells during chronic active viral infection in mice
•Deletion of socs3 in T cells prevents immune failure and promotes viral clearance
•In vivo IL-7 therapy represses Socs3 in T cells and clears chronic infection
•IL-7 promotes IL-22 production to mitigate immunopathology in chronic infection
Summary
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.
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