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.