Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease

TY - JOUR

T1 - Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease

AU - Kögl, Tamara

AU - Müller, Jürgen

AU - Jessen, Birthe

AU - Schmitt-Graeff, Annette

AU - Janka-Schaub, Gritta

AU - Ehl, Stephan

AU - zur Stadt, Udo

AU - Aichele, Peter

PY - 2013/1/24

Y1 - 2013/1/24

N2 - 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.

AB - 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.

KW - Animals

KW - Antigens, CD

KW - Antigens, CD274

KW - Cell Degranulation

KW - Cytotoxicity, Immunologic

KW - Disease Models, Animal

KW - Disease Progression

KW - Interferon-gamma

KW - Killer Cells, Natural

KW - Lymphocyte Activation

KW - Lymphocytic choriomeningitis virus

KW - Lymphohistiocytosis, Hemophagocytic

KW - Mice

KW - Mice, Knockout

KW - Qa-SNARE Proteins

KW - T-Lymphocytes

KW - T-Lymphocytes, Cytotoxic

U2 - 10.1182/blood-2012-07-441139

DO - 10.1182/blood-2012-07-441139

M3 - SCORING: Journal article

C2 - 23190531

VL - 121

SP - 604

EP - 613

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 4

ER -