title: Impaired effector memory T-cell regulation facilitates graft versus host disease in CCR7-deficient bone marrow transplant chimeras.
abstract: 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.
authors.affiliation: Division of Biopharmaceutics, Leiden Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. s.de.jager@lacdr.leidenuniv.nl
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.forename: Kirsten
authors.initials: K
authors.lastname: Canté-Barrett
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Cathrine
authors.initials: C
authors.lastname: Husberg
authors.forename: Gijs H
authors.initials: GH
authors.lastname: van Puijvelde
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.forename: Arne
authors.initials: A
authors.lastname: Yndestad
authors.forename: Jessica M E
authors.initials: JM
authors.lastname: van den Oever
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Martin
authors.initials: M
authors.lastname: Lipp
authors.forename: Jaap Jan
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: Wim E
authors.initials: WE
authors.lastname: Fibbe
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: 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*
chemical_list: C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019041:L-Selectin