Oral Presentation Lorne Infection and Immunity 2022

Caspase-8 has dual roles in regulatory T cell homeostasis that balance immunity to infection and inflammatory pathology. (#10)

Charis E Teh 1 2 , Simon Preston 1 2 , Michael Stutz 1 2 , James Cooney 1 2 , Alissa Robbins 1 2 , Lucille Rankin 1 2 , Tania Tan 1 2 , Antonia Policheni 1 2 , Cody C Allison 1 2 , Liana Mackiewicz 1 2 , Gregor Ebert 1 2 , Peggy Teh 1 2 , Gabrielle Belz 1 2 , Axel Kallies 3 , Andreas Strasser 1 2 , Marc Pellegrini 1 2 , Daniel HD Gray 1 2
  1. The Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Department of Medical Biology, Australia, The University of Melbourne, Parkville, Melbourne, Australia
  3. Immunology and Microbiology, The University of Melbourne, Melbourne, VIC, Australia

FOXP3+ regulatory T (Treg) cells suppress responses to maintain immunological tolerance, but can also impair immunity to infections and cancer. Despite their importance, mechanisms that control Treg cell survival during critical stages of inflammation remain unclear. We found that Treg cell-specific deletion of caspase 8 increased Treg cell number in steady-state, revealing a requirement for death receptor mediated apoptosis for their homeostasis. However, inflammation caused a precipitous drop in caspase-8-deficient Treg cell number, via the induction of the pseudokinase MLKL and subsequent necroptosis. This loss of Treg cells enhanced clearance of herpes virus infection and improved virological control in mice with overwhelming LCMV docile infection, at the expense of lethal autoimmunity in some animals. Furthermore, Treg cells from humans were more sensitive to pharmacological induction of necroptosis than other lymphocyte populations. Therefore, this dual role for caspase 8 in Treg cell apoptosis at steady-state versus protection from necroptosis during inflammation may represent a targetable switch to manipulate Treg cell numbers for therapeutic benefit.