title: Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation.
abstract: FoxP3(+) confers suppressive properties and is confined to regulatory T cells (T(reg)) that potently inhibit autoreactive immune responses. In the transplant setting, natural CD4(+) T(reg) are critical in controlling alloreactivity and the establishment of tolerance. We now identify an important CD8(+) population of FoxP3(+) T(reg) that convert from CD8(+) conventional donor T cells after allogeneic but not syngeneic bone marrow transplantation. These CD8(+) T(reg) undergo conversion in the mesenteric lymph nodes under the influence of recipient dendritic cells and TGF-β. Importantly, this population is as important for protection from GVHD as the well-studied natural CD4(+)FoxP3(+) population and is more potent in exerting class I-restricted and antigen-specific suppression in vitro and in vivo. Critically, CD8(+)FoxP3(+) T(reg) are exquisitely sensitive to inhibition by cyclosporine but can be massively and specifically expanded in vivo to prevent GVHD by coadministering rapamycin and IL-2 antibody complexes. CD8(+)FoxP3(+) T(reg) thus represent a new regulatory population with considerable potential to preferentially subvert MHC class I-restricted T-cell responses after bone marrow transplantation.
authors.affiliation: Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, Brisbane, Australia.
authors.forename: Renee J
authors.initials: RJ
authors.lastname: Robb
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.forename: Yana A
authors.initials: YA
authors.lastname: Wilson
authors.forename: Neil C
authors.initials: NC
authors.lastname: Raffelt
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Olver
authors.forename: Antiopi
authors.initials: A
authors.lastname: Varelias
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Alexander
authors.forename: Bianca E
authors.initials: BE
authors.lastname: Teal
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Gunter J
authors.initials: GJ
authors.lastname: Hammerling
authors.forename: Kate A
authors.initials: KA
authors.lastname: Markey
authors.forename: Motoko
authors.initials: M
authors.lastname: Koyama
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Kelli P A
authors.initials: KP
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007376:Interleukin-2 / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D000906:Antibodies; D000939:Epitopes; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D020123:Sirolimus