Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease Academic Article uri icon


MeSH Major

  • Apoptosis
  • CD8-Positive T-Lymphocytes
  • Cell Membrane
  • Ceramides
  • Graft vs Host Disease
  • Sphingomyelin Phosphodiesterase
  • T-Lymphocytes, Cytotoxic


  • Alloreactive donor cytolytic T lymphocytes play a critical role in pathophysiology of acute graft-versus-host disease (GVHD). As GVHD progression involves tumor necrosis factor superfamily receptor activation, and as apoptotic signaling for some tumor necrosis factor superfamily receptors might involve acid sphingomyelinase (ASMase)-mediated ceramide generation, we hypothesized that ASMase deletion would ameliorate GVHD. Using clinically relevant mouse models of acute GVHD in which allogeneic bone marrow and T cells were transplanted into asmase+/+ and asmase(-/-) hosts, we identify host ASMase as critical for full-blown GVHD. Lack of host ASMase reduced the acute inflammatory phase of GVHD, attenuating cytokine storm, CD8+ T-cell proliferation/activation, and apoptosis of relevant graft-versus-host target cells (hepatocytes, intestinal, and skin cells). Organ injury was diminished in asmase(-/-) hosts, and morbidity and mortality improved at 90 days after transplantation. Resistance to cytolytic T lymphocyte-induced apoptosis was found at the target cell membrane if hepatocytes lack ASMase, as hepatocyte apoptosis required target cell ceramide generation for formation of ceramide-rich macrodomains, sites concentrating proapoptotic Fas. These studies indicate a requirement for target cell ASMase in evolution of GVHD in liver, small intestines, and skin and provide potential new targets for disease management.

publication date

  • November 19, 2009



  • Academic Article



  • eng

PubMed Central ID

  • PMC2766684

Digital Object Identifier (DOI)

  • 10.1182/blood-2008-11-191148

PubMed ID

  • 19666872

Additional Document Info

start page

  • 3693

end page

  • 706


  • 114


  • 17