title: Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD.
abstract: Antigen-presenting cells (APCs) are critical for the initiation of graft-versus-host disease (GVHD), although the responsible APC subset and molecular mechanisms remain unclear. Because dendritic cells (DCs) are the most potent APCs and the NF-kB/Rel family member RelB is associated with DC maturation and potent APC function, we examined their role in GVHD. Within 4 hours of total body irradiation, RelB nuclear translocation was increased and restricted to CD11c(hi) DCs within the host APC compartment. Furthermore, the transient depletion of CD11c(hi) donor DCs that reconstitute in the second week after transplantation resulted in a transient decrease in GVHD severity. By using RelB(-/-) bone marrow chimeras as transplant recipients or RelB(-/-) donor bone marrow, we demonstrate that the induction and maintenance of GVHD is critically dependent on this transcription factor within both host and donor APCs. Critically, RelB within APCs was required for the expansion of donor helper T cell type 1 (Th1) effectors and subsequent alloreactivity, but not the peripheral expansion or function of donor FoxP3(+) regulatory T cells. These data suggest that the targeted inhibition of nuclear RelB translocation within APCs represents an attractive therapeutic strategy to dissociate effector and regulatory T-cell function in settings of Th1-mediated tissue injury.
authors.affiliation: Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, QLD 4006, Australia.
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rowe
authors.forename: Edward S
authors.initials: ES
authors.lastname: Morris
authors.forename: Tatjana
authors.initials: T
authors.lastname: Banovic
authors.forename: Helen
authors.initials: H
authors.lastname: Bofinger
authors.forename: Brendan
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.forename: Alistair L
authors.initials: AL
authors.lastname: Don
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D039521:CD11c Antigen / Q000096:biosynthesis; D002467:Cell Nucleus / Q000378:metabolism*; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells; D051841:Transcription Factor RelB / Q000096:biosynthesis*; D014158:Transcription, Genetic
chemical_list: D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D016328:NF-kappa B; C497593:RELB protein, human; D051841:Transcription Factor RelB