Format

Send to

Choose Destination
Blood. 2016 Jan 28;127(4):426-35. doi: 10.1182/blood-2015-07-659813. Epub 2015 Oct 30.

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

Author information

1
Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
2
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA;
3
Department of Pathology, Alfred I. duPont Hospital for Children, Wilmington, DE; and.
4
Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA;
5
Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Abstract

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.

PMID:
26518437
PMCID:
PMC4731846
DOI:
10.1182/blood-2015-07-659813
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center