Impaired effector memory T-cell regulation facilitates graft versus host disease in CCR7-deficient bone marrow transplant chimeras.
BACKGROUND
The development of graft versus host disease (GvHD) is one of the major challenges of bone marrow transplantations (BMTs). Although clinical symptoms of GvHD share many features with auto immune diseases, the underlying mechanisms remain unclear. Here, we examined the effects of hematopoietic CC-chemokine receptor (CCR)7 deficiency on the development of GvHD.


METHODS
Lethally irradiated C57BL/6 mice were transplanted with bone marrow cells derived from wild-type or CCR7 C57BL/6 donor mice.


RESULTS
Unlike littermate controls, CCR7 chimeras develop overt GvHD-like symptoms within 6 weeks after transplantation. Circulating CD4 and CD8 T-cell populations of CCR7 chimeras were enriched in effector memory T cells. CCR7 CD62L regulatory T-cell expansion, which typically occurs after BMT was markedly delayed in CCR7 chimeras. Furthermore, GvHD-like reactions did not occur after cotransplantation of wild-type and CCR7 bone marrow, showing that CCR7 is critically required for tolerance induction and prevention of GvHD.


CONCLUSIONS
We are the first to demonstrate that lack of CCR7 results in delayed regulatory T-cell expansion. This results in insufficient control of effector memory T-cell expansion, which eventually leads to severe tissue damage. Conceivably, therapies aimed at boosting CD4 CD62L regulatory T-cell expansion after BMT could help to control GvHD.
de Jager
Saskia C A
SC
Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. s.de.jager@lacdr.leidenuniv.nl
Canté-Barrett
Kirsten
K
Bot
Ilze
I
Husberg
Cathrine
C
van Puijvelde
Gijs H
GH
van Santbrink
Peter J
PJ
Yndestad
Arne
A
van den Oever
Jessica M E
JM
Kuiper
Johan
J
van Berkel
Theo J C
TJ
Lipp
Martin
M
Zwaginga
Jaap Jan
JJ
Fibbe
Wim E
WE
Aukrust
Pål
P
Biessen
Erik A L
EA
D000818:Animals; D015551:Autoimmunity; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000379:methods*; D049109:Cell Proliferation; D002678:Chimera / Q000378:metabolism; D006086:Graft vs Host Disease; D007156:Immunologic Memory; D019041:L-Selectin / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019041:L-Selectin