Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells
Authors
- A. Huang
- P.V. Shinde
- J. Huang
- T. Senff
- H.C. Xu
- C. Margotta
- D. Häussinger
- T.E. Willnow
- J. Zhang
- A.A. Pandyra
- J. Timm
- S. Weggen
- K.S. Lang
- P.A. Lang
Journal
- JCI Insight
Citation
- JCI Insight 4 (17): e129856
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.