Blood Journal
Leading the way in experimental and clinical research in hematology

Hemophagocytic lymphohistiocytosis (HLH) in Syntaxin-11 deficient mice: T-cell exhaustion limits fatal disease

  1. Tamara Kögl1,
  2. Jürgen Müller2,
  3. Birthe Jessen3,
  4. Annette Schmitt-Graeff4,
  5. Gritta Janka5,
  6. Stephan Ehl3,
  7. Udo zur Stadt6, and
  8. Peter Aichele1,*
  1. 1 Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Germany;
  2. 2 Research Institute, Children's Cancer Center, Hamburg, Germany;
  3. 3 Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Germany;
  4. 4 Institute of Pathology, Department of General Pathology, University of Freiburg, Germany;
  5. 5 Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Germany;
  6. 6 Center for Diagnostics, University Medical Center, Hamburg-Eppendorf, Germany
  1. * Corresponding author; email: peter.aichele{at}


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 hyperreactive CD8 T cells and continuous IFNγ 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 non-fatal disease course into fatal HLH, identifying T-cell exhaustion as an important factor for determination of disease severity in HLH.

  • Submitted July 3, 2012.
  • Accepted November 4, 2012.