Date of Award
Doctor of Philosophy (PhD)
Edward M. Behrens
Hemophagocytic syndromes represent extreme cases of uncontrolled immune activation resulting in severe disease. Dysregulated CD8+ T cell responses are implicated in the pathogenesis of hemophagocytic syndromes, although the mechanisms responsible for their hyperactivation are incompletely understood. Identification of the signals promoting CD8+ T cell-mediated inflammation are therefore crucial to inform the development of targeted immunotherapies for these diseases. Using murine models of hemophagocytic syndrome, we investigated the interaction of activated CD8+ T cells arising in the context of systemic inflammation with their surrounding environment, both in their response to antigen-independent cues and their contribution to the cytokine storm. We found that the interleukin-33/ST2 pathway plays a key role in amplifying inflammation above the threshold for fatal disease in a murine model of familial hemophagocytic lymphohistiocytosis (FHL), generated by infection of perforin-deficient mice with lymphocytic choriomeningitis virus (LCMV). ST2 intrinsically promotes LCMV-specific CD8+ and CD4+ T cell proliferation and potentiates interferon-g (IFNg) production, thereby raising systemic quantities of IFNg to lethal levels. Blockade of ST2 signaling protects FHL mice from mortality by acutely dampening the antiviral T cell response and eventually leading to CD8+ T cell exhaustion, which further protects against chronic wasting. In a different murine model of hemophagocytic syndrome, Toll-like receptor 9-induced macrophage activation syndrome, we investigated liver-infiltrating lymphocyte populations induced by systemic inflammation. We identified a unique population of effector-like interleukin-10-producing CD8+ T cells that arises independently of antigen stimulation and accumulates within damaged liver. This work demonstrates that the contribution of antigen-independent signals to CD8+ T cell activation is essential to the pathophysiology of hemophagocytic syndromes and suggests that specific blockade of these signals may provide therapeutic benefit.
Rood, Julia Elizabeth, "The Role Of Antigen-Independent Signals In Cd8+ T Cell Responses In Hemophagocytic Syndromes" (2016). Publicly Accessible Penn Dissertations. 2556.
Available for download on Monday, January 13, 2020