NK cell-intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection

PLoS Pathog. 2019 Jun 20;15(6):e1007797. doi: 10.1371/journal.ppat.1007797. eCollection 2019 Jun.

Abstract

During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Chronic Disease
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / pathology
  • Lymphocyte Activation*
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Knockout
  • Natural Cytotoxicity Triggering Receptor 1 / genetics
  • Natural Cytotoxicity Triggering Receptor 1 / immunology
  • Receptors, Fc / genetics
  • Receptors, Fc / immunology*

Substances

  • Antigens, Ly
  • Natural Cytotoxicity Triggering Receptor 1
  • Ncr1 protein, mouse
  • Receptors, Fc

Grants and funding

This study was funded by the Sofja 713 Kovalevskaja award from the Alexander von Humboldt Foundation (SKP2008 and SKP2010) and by Deutsche Forschungsgemeinschaft (DFG) grants LA1419/5-1, LA1419/7-1, LA1558/5-1, and 715 SI1558/3-1. This study was further supported by the Sonderforschungsbereich SFB974, the Transregio 716 TRR60, and the Research Training Group (RTG) 1949/1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.