title: Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation.
abstract: CD4 regulatory T cells play a critical role in establishment of immune tolerance and prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. The recovery and maintenance of regulatory T cells is dependent on homeostatic factors including the generation of naïve regulatory T cells from hematopoietic precursor cells, the proliferation and expansion of mature regulatory T cells, and the survival of regulatory T cells in vivo. In this study, quantitation of mitochondrial apoptotic priming was used to compare susceptibility of regulatory T cells, conventional CD4 T cells and CD8 T cells to intrinsic pathway apoptosis in 57 patients after allogeneic hematopoietic stem cell transplantation and 25 healthy donors. In healthy donors, regulatory T cells are more susceptible to mitochondrial priming than conventional T cells. Mitochondrial priming is increased after hematopoietic stem cell transplantation in all T-cell subsets and particularly in patients with chronic graft-versus-host disease. Regulatory T cells express high levels of CD95 and are also more susceptible than conventional T cells to apoptosis through the extrinsic pathway. However, CD95 expression and extrinsic pathway apoptosis is not increased after hematopoietic stem cell transplantation. Decreased expression of BCL2 and increased expression of BIM, a mitochondrial cell death activator protein, in regulatory T cells contributes to increased mitochondrial priming in this T-cell subset but additional factors likely contribute to increased mitochondrial priming following hematopoietic stem cell transplantation.
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Murase
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, USA Harvard School of Public Health, Boston, MA, USA.
authors.forename: Haesook T
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: O R Gregory
authors.initials: OR
authors.lastname: Bascug
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Department of Hematology and Oncology, Okayama University, Japan.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: John
authors.initials: J
authors.lastname: Koreth
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Ho
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Corey
authors.initials: C
authors.lastname: Cutler
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.affiliation: Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Medical School, Boston, MA, USA Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA, USA Harvard Stem Cell Institute, Boston, MA, USA jerome_ritz@dfci.harvard.edu.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002908:Chronic Disease; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010446:Peptide Fragments / Q000494:pharmacology*; D061251:Primary Cell Culture; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D014019:Tissue Donors; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
chemical_list: C474007:Bax protein (53-86); C491901:FAS protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor