title: Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD.
abstract: FoxP3(+) regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8(+)FoxP3(+) T cells represented approximately 70% of the iTreg pool. These CD8(+)FoxP3(+) T cells shared phenotypic markers with their CD4(+) counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4(+) and CD8(+) Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3(+) Treg pool in allogeneic recipients and their potential role in protection against GVHD.
authors.affiliation: Transfusion Medicine and Therapeutic Pathology Division, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Sawamukai
authors.forename: Atsushi
authors.initials: A
authors.lastname: Satake
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Ian T
authors.initials: IT
authors.lastname: Lamborn
authors.forename: Priti
authors.initials: P
authors.lastname: Ojha
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Taku
authors.initials: T
authors.lastname: Kambayashi
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D018125:Receptors, Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta