The cytolytic molecules Fas ligand and TRAIL are required for murine thymic graft-versus-host disease.
Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
Na
Il-Kang
IK
Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Lu
Sydney X
SX
Yim
Nury L
NL
Goldberg
Gabrielle L
GL
Tsai
Jennifer
J
Rao
Uttam
U
Smith
Odette M
OM
King
Christopher G
CG
Suh
David
D
Hirschhorn-Cymerman
Daniel
D
Palomba
Lia
L
Penack
Olaf
O
Holland
Amanda M
AM
Jenq
Robert R
RR
Ghosh
Arnab
A
Tran
Hien
H
Merghoub
Taha
T
Liu
Chen
C
Sempowski
Gregory D
GD
Ventevogel
Melissa
M
Beauchemin
Nicole
N
van den Brink
Marcel R M
MR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis; D002465:Cell Movement; D053222:Fas Ligand Protein / Q000502:physiology*; D006086:Graft vs Host Disease / Q000209:etiology* / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053262:Receptors, OX40 / Q000502:physiology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000502:physiology; D017154:Stromal Cells / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D014184:Transplantation, Homologous
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053222:Fas Ligand Protein; D053262:Receptors, OX40; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505717:Tnfrsf4 protein, mouse; C505654:Tnfsf10 protein, mouse