1. Massive activation-induced cell death of alloreactive T cells with apoptosis of bystander postthymic T cells prevents immune reconstitution in mice with graft-versus-host disease.
- Author
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Brochu S, Rioux-Massé B, Roy J, Roy DC, and Perreault C
- Subjects
- Animals, Autoimmunity, Cell Differentiation, Cell Lineage, Fas Ligand Protein, Graft vs Host Disease pathology, Membrane Glycoproteins physiology, Mice, Mice, Inbred A, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Radiation Chimera, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets transplantation, Thymus Gland cytology, Transplantation Conditioning, fas Receptor biosynthesis, Apoptosis, Bone Marrow Transplantation adverse effects, Graft vs Host Disease immunology, Lymphocyte Activation, T-Lymphocyte Subsets cytology
- Abstract
After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4(+) and CD8(+) T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non-host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non-host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.
- Published
- 1999