title: Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease.
abstract: Syntaxin-11 (Stx11), an atypical member of the SNARE protein family, is part of the cytolytic machinery of T and NK cells and involved in the fusion of lytic granules with the plasmamembrane. Functional loss of syntaxin-11 in humans causes defective degranulation and impaired cytolytic activity of T and NK cells. Furthermore, patients with STX11 deficiency develop familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a life-threatening disease of severe hyperinflammation. We established Stx11-deficient mice as an animal model for FHL4. Stx11-deficient mice exhibited severely reduced degranulation and cytolytic activity of CTL and NK cells and developed all clinical symptoms of hemophagocytic lymphohistiocytosis (HLH) after infection with lymphocytic choriomeningitis virus (LCMV). The HLH phenotype was further characterized by hyperactive CD8 T cells and continuous IFN-γ production. However, in contrast to perforin-deficient mice, which represent a model for FHL2, progression of HLH was not fatal. Survival of Stx11-deficient mice was determined by exhaustion of antigen-specific T cells, characterized by expression of inhibitory receptors, sequential loss of effector functions, and finally T-cell deletion. Blockade of inhibitory receptors on T cells in Stx11-deficient mice converted nonfatal disease course into fatal HLH, identifying T-cell exhaustion as an important factor for determination of disease severity in HLH.
authors.affiliation: Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kögl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Müller
authors.forename: Birthe
authors.initials: B
authors.lastname: Jessen
authors.forename: Annette
authors.initials: A
authors.lastname: Schmitt-Graeff
authors.forename: Gritta
authors.initials: G
authors.lastname: Janka
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.forename: Udo
authors.initials: U
authors.lastname: zur Stadt
authors.forename: Peter
authors.initials: P
authors.lastname: Aichele
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D050765:Qa-SNARE Proteins / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; D050765:Qa-SNARE Proteins; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein