Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease
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Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell exhaustion limits fatal disease. / Kögl, Tamara; Müller, Jürgen; Jessen, Birthe; Schmitt-Graeff, Annette; Janka-Schaub, Gritta; Ehl, Stephan; zur Stadt, Udo; Aichele, Peter.
In: BLOOD, Vol. 121, No. 4, 24.01.2013, p. 604-13.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -