Progranulin prevents regulatory NK cell cytotoxicity against antiviral T cells


  • 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


  • JCI Insight


  • JCI Insight 4 (17): e129856


  • `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.