Interleukin-33 is a mediator of murine familial hemophagocytic lymphohistiocytosis (IRC5P.629)

Abstract

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder caused by uncontrolled, systemic immune activation. The murine model, in which lymphocytic choriomeningitis virus (LCMV) infection of perforin knockout (PKO) mice triggers FHL, demonstrates that the disease is driven by an excess of interferon-γ (IFNγ)-producing LCMV-specific CD8+ T cells. While this overactive T cell response is thought to arise from excess antigen stimulation through the TCR, data from our lab suggest that non-TCR, MyD88-dependent signaling pathways may be equally important. We show that interleukin-33 (IL-33), a cytokine released by damaged tissue, plays a critical role in driving FHL. LCMV-infected PKO mice receiving IL-33 receptor-blocking antibody (α-IL-33R) show markedly improved survival compared to isotype-treated controls (p=0.0005) and reduced severity of multiple disease parameters, including serum IFNγ (p=0.0005). α-IL-33R-treated mice have fewer gp33-specific CD8+ T cells (p=0.0044) and total effector CD8+ T cells (p<0.0001). IL-33R blockade also reduces the frequency and IFNγ MFI of IFNγ+ gp33-specific CD8+ T cells (p=0.0004 and p=0.0016, respectively). We observe similar effects on LCMV-specific CD4+ T cells, as well. These data demonstrate that disruption of IL-33 signaling in the murine model of FHL reduces T cell-mediated production of IFNγ, leading to improved morbidity and mortality, and suggest blockade of this pathway as a viable treatment strategy for FHL.