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Caspase-8 restricts natural killer cell accumulation during MCMV Infection.
Yanjun Feng1, Lisa P Daley-Bauer1, Linda Roback1
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 23, 2019
Summary
Caspase-8 (CASP8) restricts natural killer (NK) cell expansion during murine cytomegalovirus (MCMV) infection. Its absence, along with RIPK1, amplifies NK cell accumulation and T cell crosstalk.
Area of Science:
- Immunology
- Virology
- Cell Death Signaling
Background:
- Natural killer (NK) cells are crucial for host defense against herpesviruses like murine cytomegalovirus (MCMV).
- NK cell responses involve expansion, contraction, and memory formation, tightly regulated to balance immunity and tissue damage.
- Caspase-8 (CASP8) is a protease initiating apoptosis and regulating necroptosis, inflammation, and death-independent signaling.
Purpose of the Study:
- To investigate the role of Caspase-8 (CASP8) in regulating NK cell responses during MCMV infection.
- To determine the interplay between CASP8, RIPK1, and RIPK3 in controlling NK cell expansion and T cell responses.
- To elucidate how cell death pathways influence adaptive immunity during viral infections.
Main Methods:
- Utilized Casp8-deficient (Casp8-/-) and Ripk3-deficient (Ripk3-/-) mouse models infected with MCMV.
- Analyzed NK cell expansion, memory formation, and CD8 T cell responses in various knockout mouse lines.
- Compared immune cell dynamics in Casp8-/-Ripk3-/- mice with Ripk1-/-Casp8-/-Ripk3-/- mice.
Main Results:
- CASP8 restricts NK cell expansion during MCMV infection but does not affect NK cell memory.
- Casp8-/-Ripk3-/- mice exhibit enhanced NK cell expansion, supporting greater Ly49H- NK cells and CD8 T cells.
- Hyperaccumulation of NK cells in Casp8-/-Ripk3-/- mice is dependent on the pronecrotic kinase RIPK1.
Conclusions:
- CASP8 is a key regulator of NK cell response magnitude during MCMV infection, modulated by RIPK1.
- Absence of CASP8 and RIPK1 leads to amplified NK cell accumulation and enhanced crosstalk with effector CD8 T cells.
- Extrinsic cell death machinery, regulated by CASP8 and RIPK1, plays a critical role in controlling innate and adaptive immune cell dynamics during viral infections.
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