Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells

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Item Type:	Article
Title:	Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells
Creators Name:	Huang, A., Shinde, P.V., Huang, J., Senff, T., Xu, H.C., Margotta, C., Häussinger, D., Willnow, T.E., Zhang, J., Pandyra, A.A., Timm, J., Weggen, S., 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
ISSN:	2379-3708
Publisher:	American Society for Clinical Investigation
Volume:	4
Number:	17
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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