Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease.
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.
Rotolo
Jimmy A
JA
Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Stancevic
Branka
B
Lu
Sydney X
SX
Zhang
Jianjun
J
Suh
David
D
King
Christopher G
CG
Kappel
Lucy W
LW
Murphy
George F
GF
Liu
Chen
C
Fuks
Zvi
Z
van den Brink
Marcel R
MR
Kolesnick
Richard
R
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002518:Ceramides / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D016513:Mice, SCID; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D002518:Ceramides; D016207:Cytokines; D007371:Interferon-gamma; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase