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Caspase-8-dependent control of NK- and T cell responses during cytomegalovirus infection

Yanjun Feng1, Lisa P Daley-Bauer1, Edward S Mocarski2

  • 1Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 1462 Clifton Rd. N.E, Atlanta, GA, 30322, USA.

Medical Microbiology and Immunology
|May 18, 2019
PubMed

Insights

Caspase-8 (CASP8) restrains antiviral immunity by limiting natural killer (NK) and CD8 T cell expansion during murine cytomegalovirus (MCMV) infection. This host defense mechanism is independent of RIPK3-regulated pathways, highlighting CASP8

Area of Science:

  • Immunology
  • Virology
  • Cell Biology

Background:

  • Caspase-8 (CASP8) plays a complex role in antiviral immunity.
  • Extrinsic apoptosis and necroptosis pathways are crucial for host defense against viruses like murine cytomegalovirus (MCMV).
  • Mice lacking both CASP8 and RIPK3 allow for the study of CASP8 functions without interference from necroptosis.

Purpose of the Study:

  • To investigate the specific role of Caspase-8 (CASP8) in antiviral immunity against MCMV.
  • To understand how CASP8 influences the expansion, contraction, and memory formation of natural killer (NK) and CD8 T cells during MCMV infection.
  • To determine the interplay between CASP8, RIPK3, and interferon-gamma (IFNγ) in controlling MCMV persistence.

Main Methods:

  • Utilized genetically modified mice with deficiencies in CASP8, RIPK3, and RIPK1.
  • Administered MCMV infection to assess antiviral immune responses.
  • Quantified virus-specific NK and CD8 T cell populations, proliferation, contraction, and memory formation.
  • Analyzed the impact of IFNγ signaling on MCMV control in the absence of CASP8 and RIPK3.

Main Results:

  • Mice lacking CASP8 and RIPK3 exhibited robust antiviral T cell responses and controlled MCMV infection.
  • CASP8 deficiency led to increased expansion of MCMV-specific NK and CD8 T cells without affecting contraction or memory.
  • While CD8 T cell memory developed, MCMV-associated memory inflation was reduced in CASP8-deficient mice.
  • Mice lacking CASP8 and RIPK3 showed increased dependence on IFNγ for sustained MCMV control, with higher viral persistence in the absence of IFNγ signaling.

Conclusions:

  • Host CASP8 function is critical for appropriate NK and T cell immunity to MCMV, operating independently of RIPK3-regulated pathways.
  • CASP8 acts as a brake on the expansion phase of antiviral CD8 T cell responses.
  • Effective long-term control of MCMV relies on a balance between CASP8-mediated regulation and IFNγ-dependent mechanisms.
Keywords:
ApoptosisCell deathHerpesvirusNecroptosisProliferationRipoptosome

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