title: ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice.
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.
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rood
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Sheila
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Michele
authors.initials: M
authors.lastname: Paessler
authors.affiliation: Department of Pathology, Alfred I. duPont Hospital for Children, Wilmington, DE; and.
authors.forename: Portia A
authors.initials: PA
authors.lastname: Kreiger
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Niansheng
authors.initials: N
authors.lastname: Chu
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Erietta
authors.initials: E
authors.lastname: Stelekati
authors.affiliation: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: E John
authors.identifier: http://orcid.org/0000-0003-0477-1956
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: Division of Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, PA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
authors.forename: Edward M
authors.initials: EM
authors.lastname: Behrens
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D017353:Gene Deletion; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008216:Lymphocytic Choriomeningitis / Q000150:complications / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000276:immunology* / Q000473:pathology* / Q000628:therapy / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D054353:Perforin / Q000235:genetics; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D018123:Receptors, Interleukin; C510467:perforin 1, mouse; D054353:Perforin; D007371:Interferon-gamma