title: Host-derived CD8⁺ dendritic cells protect against acute graft-versus-host disease after experimental allogeneic bone marrow transplantation.
abstract: Graft-versus-host disease (GVHD) is a frequent life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT) and induced by donor-derived T cells that become activated by host antigen-presenting cells. To address the relevance of host dendritic cell (DC) populations in this disease, we used mouse strains deficient in CD11c(+) or CD8α(+) DC populations in a model of acute GVHD where bone marrow and T cells from BALB/c donors were transplanted into C57BL/6 hosts. Surprisingly, a strong increase in GVHD-related mortality was observed in the absence of CD11c(+) cells. Likewise, Batf3-deficient (Batf3(-/-)) mice that lack CD8α(+) DCs also displayed a strongly increased GVHD-related mortality. In the absence of CD8α(+) DCs, we detected an increased activation of the remaining DC populations after HSCT, leading to an enhanced priming of allogeneic T cells. Importantly, this was associated with reduced numbers of regulatory T cells and transforming growth factor-β levels, indicating an aggravated failure of peripheral tolerance mechanisms after HSCT in the absence of CD8α(+) DCs. In summary, our results indicate a critical role of CD8α(+) DCs as important inducers of regulatory T cell-mediated tolerance to control DC activation and T cell priming in the initiation phase of GVHD.
authors.affiliation: Institute of Immunology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Weber
authors.affiliation: Department of Dermatology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Berenice
authors.initials: B
authors.lastname: Rudolph
authors.affiliation: Institute of Immunology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Pamela
authors.initials: P
authors.lastname: Stein
authors.affiliation: Institute of Molecular Medicine, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.affiliation: IIIrd Department of Medicine, Johannes Gutenberg-University Medical Center, Mainz, Germany; Center for Thrombosis and Hemostasis, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bosmann
authors.affiliation: Institute of Immunology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.affiliation: IIIrd Department of Medicine, Johannes Gutenberg-University Medical Center, Mainz, Germany. Electronic address: radsak@uni-mainz.de.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous / Q000379:methods*
keywords: BATF3; Dendritic cells; Graft-versus-host disease; Hematopoietic stem cell transplantation