Abstract
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.
Highlights
Hemophagocytic lymphohistiocytosis is a disease of dysregulated hyperinflammation that results from an immunogenic trigger in the context of inadequate negative regulatory mechanisms [1]
Given the association of CD8+ T cell exhaustion with long-term survival in murine FHL type 4 (FHL4), we first determined whether the prosurvival effect of ST2 blockade enables development of CD8+ T cell exhaustion in murine familial hemophagocytic lymphohistiocytosis type 2 (FHL2)
We show that blockade of IL-33 signaling intrinsically attenuates proliferation and cytokine production of lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cells in murine FHL2 early in the course of disease
Summary
Hemophagocytic lymphohistiocytosis is a disease of dysregulated hyperinflammation that results from an immunogenic trigger in the context of inadequate negative regulatory mechanisms [1]. Chronic defects in CD8+ T cell function have been implicated as a protective negative regulatory mechanism in the related murine model of FHL type 4 (FHL4) [9]. In these syntaxin-11-deficient (Stx11−/−) mice, disease develops transiently following LCMV infection but gradually becomes quiescent as the CD8+ T cell pool undergoes a functional decline known as exhaustion. Whether a similar mechanism occurs in other murine models of FHL has not been shown
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