title: TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment.
abstract: CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) have been shown to effectively prevent graft-versus-host disease (GVHD) when adoptively transferred in murine models of hematopoietic cell transplantation and in phase 1/2 clinical trials. Critical limitations to Treg clinical application are the paucity of cells and limited knowledge of the mechanisms of in vivo function. We hypothesized that inflammatory conditions in GVHD modify Treg characteristics and activity. We found that peripheral blood of recipient animals during acute GVHD (aGVHD) induces Treg activation and enhances their function. The serum contains high levels of tumor necrosis factor-α (TNF-α) that selectively activates Tregs without impacting CD4(+)FoxP3(-) T cells. TNF-α priming induces Treg in vivo proliferation, whereas it limits the ability of CD4 and CD8 conventional T cells (Tcons) to proliferate and induce GVHD. TNF-α-primed Tregs prolong animal survival as compared with unprimed Tregs when used at an unfavorable Treg:Tcon ratio, demonstrating enhanced in vivo efficacy of TNF-α-primed Tregs. Because TNF-α is produced by several immune cells during inflammation, our work elucidates aspects of the physiologic mechanisms of Treg function. Furthermore, TNF-α priming of Tregs provides a new tool to optimize Treg cellular therapies for GVHD prevention and treatment.
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and Hematopoietic Stem Cell Transplantation Program, Division of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Antonio
authors.identifier: 0000-0003-3518-0665
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: William
authors.initials: W
authors.lastname: Strober
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Moffett
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishikii
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Maite
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Everett
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA; and.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D008213:Lymphocyte Activation; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha