Disruption of IL-33 Signaling Limits Early CD8+ T Cell Effector Function Leading to Exhaustion in Murine Hemophagocytic Lymphohistiocytosis

Danger signals mediated through ST2, the interleukin-33 (IL-33) receptor, amplify CD8+ T cell-mediated inflammation in the murine model of familial hemophagocytic lymphohistiocytosis type 2 (FHL2), and blockade of ST2 provides a potential therapeutic strategy in this disease. However, the long-term effects of disrupting IL-33/ST2 signaling on the CD8+ T cell compartment are unknown. Here, we examined the evolution of the T cell response in murine FHL type 2 in the absence of ST2 signaling and found that CD8+ T cells gradually undergo exhaustion, similar to a related nonfatal FHL model. ST2 inhibition indirectly promotes CD8+ T cell exhaustion, and in contrast to other forms of FHL, reversal of exhaustion does not affect mortality. Disruption of IL-33 signaling exerts a more significant impact on the CD8+ T cell compartment early in the course of disease by intrinsically limiting CD8+ T cell proliferative and cytokine production capacity. Our data thus suggest that while ST2 blockade ultimately enables the development of CD8+ T cell exhaustion in late-stage murine FHL2, exhaustion is merely an effect, rather than the cause, of extended survival in these mice. The acute impact of ST2 inhibition on both the quantity and quality of the effector CD8+ T cell response more likely underlies the protective benefits of this treatment. This study provides evidence that redefines the relationship between CD8+ T cell exhaustion and mortality in murine FHL and supports the therapeutic use of ST2 blockade during the acute stage of disease

CXCL9 inhibition does not ameliorate disease in murine models of both primary and secondary hemophagocytic lymphohistiocytosis

Abstract Hemophagocytic Lymphohistiocytosis (HLH) is a group of disorders culminating in systemic inflammation and multi-organ failure with high incidence of hepatic dysfunction. Overproduction of IFN-γ is the main immunopathological driver in this disorder. Monokine induced by IFN-γ (CXCL9) serves as a biomarker for disease activity and response to treatment in this disorder. However, very little is understood about the actual functional role of CXCL9 in pathogenesis in HLH. In the current study, we sought to determine the role of CXCL9 in pathogenesis in murine models of both Familial HLH (prf1 −/− ) and Toll Like Receptor (TLR) 9 repeated stimulation induced Macrophage Activation Syndrome (MAS), a form of secondary HLH. FHL and MAS were induced in both CXCL9 genetically deficient mice (cxcl9 −/− ) and controls as well as using AMG487, a pharmacological antagonist of the CXCL9 receptor, CXCR3. Results showed that CXCL9 genetic deficiency did not improve disease parameters or hepatitis in both models. Consistent with genetic ablation of CXCL9, inhibition of its receptor, CXCR3, by AMG487 did not show any significant effects in the FHL model. Taken together, inhibition of CXCL9-CXCR3 interaction does not ameliorate HLH physiology in general, or hepatitis as a classical target organ of disease

ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice

Cytokine storm syndromes, such as familial hemophagocytic lymphohistiocytosis (FHL), are lethal disorders caused by uncontrolled, systemic immune activation. In the murine model of FHL, in which perforin-deficient (Prf1(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV), disease is driven by overabundant interferon (IFN)γ-producing LCMV-specific CD8(+) T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However, this paradigm is insufficient to explain several fundamental aspects of FHL, namely, the inability of many pathogenic antigens to induce hyperinflammation, and the previously identified role of MyD88 in the disease. We now show a novel role for the MyD88-dependent interleukin-33 (IL-33) receptor, ST2, in FHL. Expression of IL-33 and ST2 is upregulated in LCMV-infected Prf1(-/-) mice. Blockade of ST2 markedly improves survival of LCMV-infected Prf1(-/-) mice and reduces the severity of multiple disease parameters, including serum levels of IFNγ. This decrease in IFNγ corresponds to a reduction in both the frequency of IFNγ(+) LCMV-specific CD8(+) and CD4(+) T cells and the magnitude of IFNγ expression in these cells. These findings demonstrate that disruption of ST2 signaling in the murine model of FHL reduces T cell-mediated production of IFNγ and suggest a revised paradigm in which danger signals such as IL-33 are crucial amplifiers of immune dysregulation in FHL. Furthermore, this study provides evidence to support blockade of ST2 as a novel therapeutic strategy for FHL