Caspase-8 restricts antiviral CD8 T cell hyperaccumulation.
Yanjun Feng1, Lisa P Daley-Bauer1, Linda Roback1
1Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30033.
Summary
Caspase-8 (CASP8) restricts CD8 T cell proliferation during viral infections. Removing CASP8 enhances T cell expansion, revealing its cell-autonomous role in limiting immune responses.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- CD8 T cell response magnitude is regulated by proliferation and death.
- Caspase-8 (CASP8) influences apoptosis, necroptosis, and cell death-independent signaling.
- RIPK3 is involved in necroptosis, a programmed form of necrosis.
Purpose of the Study:
- To investigate the role of Caspase-8 (CASP8) in regulating CD8 T cell responses during viral infections.
- To determine if CASP8's function is cell-autonomous and independent of RIPK3-mediated necroptosis.
- To analyze the impact of CASP8 deficiency on T cell expansion, differentiation, and memory formation.
Main Methods:
- Mice deficient in CASP8 and RIPK3 (Casp8-/-Ripk3-/-) were infected with murine cytomegalovirus (MCMV) or herpes simplex virus-1.
- Flow cytometry was used to analyze CD8 T cell populations, including terminally differentiated effector cells (KLRG1hi).
- Adoptive transfer of splenocytes from infected Casp8-/-Ripk3-/- mice into wild-type (WT) recipients assessed T cell proliferation.
Main Results:
- Casp8-/-Ripk3-/- mice showed enhanced peak CD8 T cell levels against MCMV and HSV-1 compared to controls.
- Higher peak responses in Casp8-/-Ripk3-/- mice were due to increased accumulation of KLRG1hi effector CD8 T cells.
- Antiviral CD8 T cells from Casp8-/-Ripk3-/- mice exhibited enhanced proliferation in WT recipients, indicating cell-autonomous restriction by CASP8.
- MCMV-specific memory inflation was not sustained long-term in Casp8-/-Ripk3-/- mice, despite retained immunity.
- Chronic MCMV infection reduced the accumulation of abnormal B220+CD3+ T cells in viable CASP8-deficient mice.
Conclusions:
- Cell-autonomous CASP8 normally restricts CD8 T cell proliferation following T cell receptor activation.
- CASP8 plays a critical role in regulating the magnitude of antiviral CD8 T cell expansion.
- The absence of RIPK3-mediated necroptosis uncovers a cell death-independent function of CASP8 in CD8 T cell expansion.
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