title: Origin of Enriched Regulatory T Cells in Patients Receiving Combined Kidney-Bone Marrow Transplantation to Induce Transplantation Tolerance.
abstract: We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney-bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-β hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3+CD4+CD25highCD127lowFoxp3+) in blood that resulted from peripheral proliferation (Ki67+), possibly new thymic emigration (CD31+), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4+and CD8+cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.|Laboratory of Experimental Transplantation, Department of Microbiology and Immunology, Department of Nephrology, KU Leuven-University of Leuven, University Hospitals Leuven, Leuven, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Sprangers
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: S
authors.initials: S
authors.lastname: DeWolf
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: T M
authors.initials: TM
authors.lastname: Savage
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: T
authors.initials: T
authors.lastname: Morokata
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: A
authors.initials: A
authors.lastname: Obradovic
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: S A
authors.initials: SA
authors.lastname: LoCascio
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: B
authors.initials: B
authors.lastname: Shonts
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: J
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: S P
authors.initials: SP
authors.lastname: Lau
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: R
authors.initials: R
authors.lastname: Shah
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: H
authors.initials: H
authors.lastname: Morris
authors.affiliation: Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: V
authors.initials: V
authors.lastname: Steshenko
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: E
authors.initials: E
authors.lastname: Zorn
authors.affiliation: Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: F I
authors.initials: FI
authors.lastname: Preffer
authors.affiliation: Epiontis GmbH, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Olek
authors.affiliation: Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: D M
authors.initials: DM
authors.lastname: Dombkowski
authors.affiliation: Center for Translational Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA.|Immune Tolerance Network, Seattle, WA.
authors.forename: L A
authors.initials: LA
authors.lastname: Turka
authors.affiliation: Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: R
authors.initials: R
authors.lastname: Colvin
authors.affiliation: Division of Rheumatology, Department of Medicine, Columbia University Medical Center, New York, NY.
authors.forename: R
authors.initials: R
authors.lastname: Winchester
authors.affiliation: Transplantation Unit, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA.
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY.|Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA.|Department of Microbiology & Immunology, Columbia University Medical Center, Columbia University, New York, NY.|Department of Surgery, Columbia University Medical Center, Columbia University, New York, NY.
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D016026:Bone Marrow Transplantation; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016030:Kidney Transplantation; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018183:Transplantation Chimera / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell
keywords: T cell biology; cellular biology; immunobiology; kidney transplantation/nephrology; tolerance; translational research/science