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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2016)

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.

    Cover page: The role of caspase-8 in regulating dendritic cell activation during both homeostasis and chronic viral infection
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2018)
    Caspase-8 (CASP8) is known as an executioner of apoptosis, but more recent studies have shown that it participates in the regulation of necroptosis and innate immunity. In this study, we show that CASP8 negatively regulates retinoic acid-inducible gene I (RIG-I) signaling such that, in its absence, stimulation of the RIG-I pathway in dendritic cells (DCs) produced modestly enhanced activation of IFN regulatory factor 3 with correspondingly greater amounts of proinflammatory cytokines. In addition, mice lacking DC-specific CASP8 (dcCasp8-/- mice) develop age-dependent symptoms of autoimmune disease characterized by hyperactive DCs and T cells, spleen and liver immunopathology, and the appearance of Th1-polarized CD4+ T cells. Such mice infected with chronic lymphocytic choriomeningitis virus, an RNA virus detected by RIG-I, mounted an enhanced lymphocytic choriomeningitis virus-specific immune response as measured by increased proportions of Ag-specific CD4+ T cells and multicytokine-producing CD4+ and CD8+ T cells. These results show that CASP8 subtly modulates DC maturation, which controls the spontaneous appearance of autoimmune T cells while simultaneously attenuating the acquired immune system and its potential to control a persistent viral infection.
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