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Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells

Item Type:Article
Title:Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells
Creators Name:Huang, A. and Shinde, P.V. and Huang, J. and Senff, T. and Xu, H.C. and Margotta, C. and Häussinger, D. and Willnow, T.E. and Zhang, J. and Pandyra, A.A. and Timm, J. and Weggen, S. and Lang, K.S. and Lang, P.A.
Abstract:`NK cell-mediated regulation of antigen-specific T cells can contribute to and exacerbate chronic viral infection, but the protective mechanisms against NK cell-mediated attack on T cell immunity are poorly understood. Here, we show that progranulin (PGRN) can reduce NK cell cytotoxicity through reduction of NK cell expansion, granzyme B transcription, and NK cell-mediated lysis of target cells. Following infection with the lymphocytic choriomeningitis virus (LCMV), PGRN levels increased - a phenomenon dependent on the presence of macrophages and type I IFN signaling. Absence of PGRN in mice (Grn(-/-)) resulted in enhanced NK cell activity, increased NK cell-mediated killing of antiviral T cells, reduced antiviral T cell immunity, and increased viral burden, culminating in increased liver immunopathology. Depletion of NK cells restored antiviral immunity and alleviated pathology during infection in Grn(-/-) mice. In turn, PGRN treatment improved antiviral T cell immunity. Taken together, we identified PGRN as a critical factor capable of reducing NK cell-mediated attack of antiviral T cells.
Keywords:Animal Disease Models, Antiviral Agents, CD8-Positive T-Lymphocytes, Cyclin T, Cyclin-Dependent Kinase 9, HEK293 Cells, Immunologic Cytotoxicity, Inbred C57BL Mice, Knockout Mice, Liver, Lymphocyte Activation, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Macrophages, Natural Killer Cells, Progranulins, T-Lymphocytes, Virus Diseases, Animals, Mice
Source:JCI Insight
Publisher:American Society for Clinical Investigation
Page Range:e129856
Date:5 September 2019
Official Publication:https://doi.org/10.1172/jci.insight.129856
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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