Date of Award


Degree Type


Degree Name

Doctor of Philosophy (PhD)

Graduate Group


First Advisor

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.

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