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 7

NK cell depletion restores defective T Cell immunity and prevents pathology in Grn–/– mice.

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NK cell depletion restores defective T Cell immunity and prevents pathol...
(A and B) WT and Grn–/– mice were infected with 2 × 106 LCMV. Splenocytes were collected and incubated with RMA/S cells for 16 hours. (A) IFN-γ+ NK cells were measured by flow cytometry (n = 8–15). (B) NK cell–mediated killing to RMA/S cells were measured (n = 12–14). (C) WT and Grn–/– mice were transferred with 1 × 106 P14 T cells, followed by infection with 2 × 106 pfu LCMV. The frequency (left panel) and cell numbers (right panel) of apoptotic P14 cells were determined at day 2 after infection. (n = 5–6). (D–I) WT and Grn–/– mice were treated with anti-NK1.1 (αNK1.1) antibody, followed by infection with 2 × 106 pfu WE. (D) Gp33-specific CD8+ T cells were determined by flow cytometry in blood samples from all groups, as indicated at the specified time points after infection (n = 5–8. *P < 0.05 between Grn–/– and WT group). (E) IFN-γ+CD8+ T cells were measured by flow cytometry following gp33 peptide stimulation (n = 8–10). n.c. represents negative control. (F) Virus titers were measured in indicated organs at day 12 after infection (n =8–9). (G) Sections of snap-frozen liver tissue (day 12 after infection) were analyzed for LCMV-NP expression (n = 6–8). Right panel indicates quantification of fluorescence intensity. Scale bars: 50 μm. (H) Serum AST (left panel) and ALT (right panel) activities were measured at day 8 after infection (n = 4–5). (I) Sections of snap-frozen liver tissue harvested from all groups as indicated 12 days after infection were stained with α-SMA (n = 6–8). Right panel indicates quantification of fluorescence intensity. Scale bars: 50μm. Data show mean ± SEM. Each symbol represents an individual mouse. P values calculated by 2-way ANOVA (except for C by Student’s t test), *P < 0.05; **P < 0.001; ***P < 0.001; ****P < 0.0001; ns, not statistically significant between the indicated groups.