Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation
Kazuyuki Murase,
Haesook T. Kim,
O.R. Gregory Bascug,
Yutaka Kawano,
Jeremy Ryan,
Ken-ichi Matsuoka,
Matthew S. Davids,
John Koreth,
Vincent T. Ho,
Corey Cutler,
Philippe Armand,
Edwin P. Alyea,
Bruce R. Blazar,
Joseph H. Antin,
Robert J. Soiffer,
Anthony Letai,
Jerome Ritz
Affiliations
Kazuyuki Murase
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Haesook T. Kim
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
O.R. Gregory Bascug
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Yutaka Kawano
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Jeremy Ryan
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Ken-ichi Matsuoka
Department of Hematology and Oncology, Okayama University, Japan
Matthew S. Davids
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
John Koreth
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Vincent T. Ho
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Corey Cutler
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Philippe Armand
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Edwin P. Alyea
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Bruce R. Blazar
Masonic Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA
Joseph H. Antin
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Robert J. Soiffer
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Anthony Letai
Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Harvard Medical School, Boston, MA, USA
Jerome Ritz
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
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.
