Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation

Haematologica. 2014 Sep;99(9):1499-508. doi: 10.3324/haematol.2014.104166. Epub 2014 May 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Apoptosis
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • Case-Control Studies
  • Chronic Disease
  • Female
  • Gene Expression
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / pathology
  • Graft vs Host Disease / therapy
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Male
  • Middle Aged
  • Mitochondria / drug effects*
  • Mitochondria / immunology
  • Mitochondria / pathology
  • Myeloproliferative Disorders / immunology*
  • Myeloproliferative Disorders / pathology
  • Myeloproliferative Disorders / therapy
  • Peptide Fragments / pharmacology*
  • Primary Cell Culture
  • Proto-Oncogene Proteins / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / immunology
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Tissue Donors
  • Transplantation, Homologous
  • fas Receptor / genetics
  • fas Receptor / immunology


  • Bax protein (53-86)
  • FAS protein, human
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • fas Receptor