Cyclophilin D Regulates Antiviral CD8 + T Cell Survival in a Cell-Extrinsic Manner

Immunohorizons. 2020 Apr 24;4(4):217-230. doi: 10.4049/immunohorizons.2000016.


CD8+ T cell-mediated immunity is critical for host defense against viruses and requires mitochondria-mediated type I IFN (IFN-I) signaling for optimal protection. Cyclophilin D (CypD) is a mitochondrial matrix protein that modulates the mitochondrial permeability transition pore, but its role in IFN-I signaling and CD8+ T cell responses to viral infection has not been previously explored. In this study, we demonstrate that CypD plays a critical extrinsic role in the survival of Ag-specific CD8+ T cell following acute viral infection with lymphocytic choriomeningitis virus in mice. CypD deficiency resulted in reduced IFN-I and increased CD8+ T cell death, resulting in a reduced antiviral CD8+ T cell response. In addition, CypD deficiency was associated with an increase in pathogen burden at an early time-point following infection. Furthermore, our data demonstrate that transfer of wild-type macrophages (expressing CypD) to CypD-deficient mice can partially restore CD8+ T cell responses. These results establish that CypD plays an extrinsic role in regulating optimal effector CD8+ T cell responses to viral infection. Furthermore, this suggests that, under certain circumstances, inhibition of CypD function may have a detrimental impact on the host's ability to respond to viral infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods
  • Animals
  • CD8 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Survival / genetics*
  • Cyclophilin D / genetics
  • Cyclophilin D / metabolism*
  • Female
  • Host Microbial Interactions / genetics*
  • Host Microbial Interactions / immunology
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / therapy
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / immunology
  • Mitochondria / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / genetics


  • CD8 Antigens
  • Cyclophilin D
  • PPIF protein, mouse
  • Receptors, Antigen, T-Cell