Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells.

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.

• Authors: Anfei Huang, Prashant V Shinde, Jun Huang, Tina Senff, Haifeng C Xu, Cassandra Margotta, Dieter Häussinger, Thomas E Willnow, Jinping Zhang, Aleksandra A Pandyra, Jörg Timm, Sascha Weggen, Karl S Lang, Philipp A Lang
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 17 (09 05 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31484831 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Cyclin T
• Progranulins
• Cdk9 protein, mouse
• Cyclin-Dependent Kinase 9

Topics

• Animals
• Antiviral Agents (pharmacology)
• CD8-Positive T-Lymphocytes
• Cyclin T
• Cyclin-Dependent Kinase 9 (metabolism)
• Cytotoxicity, Immunologic (drug effects, immunology)
• Disease Models, Animal
• HEK293 Cells
• Humans
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Liver (immunology, pathology)
• Lymphocyte Activation (drug effects)
• Lymphocytic Choriomeningitis (immunology)
• Lymphocytic choriomeningitis virus
• Macrophages (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Progranulins (genetics, metabolism, pharmacology)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Virus Diseases