The role of caspase-8 in regulating dendritic cell activation during both homeostasis and chronic viral infection
- Author(s): Tsau, Jennifer S.
- Advisor(s): Hedrick, Stephen
- et al.
Chapter I introduces the innate and adaptive immune systems, which serve as the context for my dissertation, as well as the protein of interest in both systems.
Chapter II is a reprint of a study on which I was the second author. In this study, we investigated the role of caspase-8 in T cell survival. Caspase-8 deficient T cells were found to accumulate defectively in response to antigenic stimulation in vitro, and mice with caspase-8 deficient T cells (tCasp8-/- mice) were unable to mount a response to an acute viral infection. Inhibition of Ripk1 kinase was shown to rescue this accumulation defect in vitro, and this form of death was termed necroptosis due to its dependence upon Ripk1 and lack of shared morphological characteristics with apoptosis. However, it was unclear whether other proteins were also required for necroptosis. Both programmed necrosis (as defined by a requirement for cyclophilin D) and autophagy (as defined by a requirement for Atg7) had been proposed to play a role in T cell necroptosis. Ripk3 had also been shown to interact with Ripk1 and trigger programmed necrosis. We used genetic studies to show that while neither cyclophilin D nor Atg7 could rescue the accumulation defect of caspase-8 deficient T cells, Ripk3 did. Only mice with caspase-8 deficient T cells and an additional loss of Ripk3 (DKO mice) were able to mount a response to an acute viral infection. We also found that DKO mice developed a lymphoproliferative disease with similarities to lpr mice, which have a lupus-like autoimmune disease.
Chapter III examines the role of caspase-8 in another type of immune cell, dendritic cells (DCs). Caspase-8 was shown to negatively regulate the Rig-I innate immune signaling pathway, which produces type I interferons in response to RNA viruses. I found that mice with caspase-8 deficient DCs (dcCasp8-/- mice) develop an age-dependent autoimmunity characterized by hyperactivated DCs and T cells, organ immunopathology, and helper T cells that skew towards a Th1 phenotype. Since DC activation is considered required for a robust T cell response to viral infection, we next infected dcCasp8-/- mice with a chronic virus and found that they had an enhanced virus-specific T cell response characterized by less exhausted T cells and lower viral loads. Caspase-8 deficient DCs appeared to hyperactivate in response to Rig-I stimulation, which was likely dependent on endogenous activation of both IRF3 and NF-kB in the absence of caspase-8.