Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Distinct apoptotic pathways control regulatory T cell survival and death during chronic viral infection (#26)

Charis Teh 1 2 , Simon Preston 1 2 , Marc Pellegrini 1 2 , Andreas Strasser 1 2 , Daniel Gray 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

Foxp3+ regulatory T (Treg) cells have emerged as a crucial population that maintains the balance between tissue-damaging and protective effects in the immune system. The immunosuppressive functions of Treg cells are important in controlling autoimmunity and chronic viral infections; however, the death and survival programs that control the Treg cell pool during infection are unknown. In this study, we examined how two distinct pathways of apoptosis, the intrinsic and extrinsic apoptotic pathways, impinge on Treg cells homeostasis and function under steady-state conditions and during chronic inflammatory conditions.

To address this issue, we generated mice with a Treg cell-specific deletion of key mediators of the intrinsic (BaxΔFoxP3Bak-/-) or extrinsic (Caspase 8ΔFoxP3) apoptotic pathways. Unexpectedly, Treg cell-specific ablation of both pathways, individually, resulted in a marked increase in FoxP3+ Treg cells with an effector phenotype (CD62LlowPD1hiICOShi) in steady state conditions, suggesting dual control mechanisms in Treg cell homeostasis. Infection with the fast-replicating chronic lymphocytic choriomeningitis virus (LCMV) Docile triggered a massive expansion in the Treg cell population in wild-type and BaxΔFoxP3Bak-/- eight days post-infection, consistent with the notion that Treg cells can limit the immunopathology resulting from excessive inflammation. By contrast, the Treg cell-specific abrogation of Caspase 8 resulted in a striking decrease in Treg cell numbers and increase in non-virus-specific CD8 and CD4 cell activation.

Taken together, these data reveals that the intrinsic and extrinsic apoptotic pathways are both vital for Treg homeostasis in the steady state. By contrast, these pathways have divergent roles in the control of Treg cell function under chronic inflammatory conditions. Understanding how these pathways affect Treg cells and the immune response is pivotal because drugs that target these pathways are currently in clinical trials for treatment of cancers and autoimmune disease and knowledge about how blockade of these pathways will impact on Treg cells following infection is lacking.