Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells
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
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
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Research Article Immunology Infectious disease

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

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Figure 5

Grn deficiency limits CD8+ T cell immunity and triggers LCMV-induced immunopathology.

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Grn deficiency limits CD8+ T cell immunity and triggers LCMV-induced im...
WT and Grn–/– mice were infected with 2 × 106 pfu LCMV-WE. (A) Absolute numbers of antiviral CD8+ T cells in the blood were determined at the indicated time points after infection (n = 7–10). (B) The expression of surface molecules on spleen antiviral CD8+ T cells was examined by flow cytometry. (C) At day 12 after infection, splenocytes were restimulated with the LCMV-specific epitope gp33, followed by staining for IFN-γ (n = 7–10). n.c. indicates negative control. (D) Virus titers were determined from spleen, liver, lung, kidney, spinal cord (SC), and brain tissues at day 12 after infection (n = 7–10). (E) Sections of snap-frozen liver tissue from WT and Grn–/– mice (day 12 after infection) were analyzed for LCMV nucleoprotein (LCMV-NP) expression by IHC. The bar graph depicts the fluorescence intensity of LCMV-NP (n = 6). Scale bars: 50 μm. (F) ALT activity in the serum of control and Grn–/– mice was determined at the indicated time points after infection (n = 6). (G–I) WT mice were injected with PGRN at the indicated dose and time points (G, left panel); the absolute number of antiviral T cells in blood (G, right panel) were measured by flow cytometry (n = 7–10). (H) The absolute number of antiviral T cells in the spleen were measured by flow cytometry at day 8 (n = 7–10). (I) Splenocytes were restimulated with gp33 peptides and IFN-γ+CD8+ T cells were measured by flow cytometry (n = 7–10). Data show mean ± SEM. Each symbol represents an individual mouse. P values calculated by 2-way ANOVA (A, C, F, G, I) and Student’s t test (D, E, and H), *P < 0.05; **P < 0.001; ***P < 0.001; ****P < 0.0001.