Caspase-8 has dual roles in regulatory T cell homeostasis balancing immunity to infection and collateral inflammatory damage
- Author(s)
- Teh, CE; Preston, SP; Robbins, AK; Stutz, MD; Cooney, J; Clark, MP; Policheni, AN; Allison, CC; Mackiewicz, L; Arandjelovic, P; Ebert, G; Doerflinger, M; Tan, T; Rankin, LC; Teh, PP; Belz, GT; Kallies, A; Strasser, A; Pellegrini, M; Gray, DHD;
- Details
- Publication Year 2022-03-25,Volume 7,Issue #69,Page eabn8041
- Journal Title
- Science Immunology
- Abstract
- Targeting the potent immunosuppressive properties of FOXP3(+) regulatory T cells (T(regs)) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling T(reg) homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of T(reg) homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in T(regs) led to accumulation of effector T(regs) resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8-deficient lymphoid and tissue T(regs), which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human T(regs) have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in T(regs) that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.
- Publisher
- AAAS
- Research Division(s)
- Immunology; Blood Cells And Blood Cancer; Infectious Diseases And Immune Defence
- PubMed ID
- 35333545
- Publisher's Version
- https://doi.org/10.1126/sciimmunol.abn8041
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-04-08 10:53:30
Last Modified: 2022-04-08 11:19:40