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.
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.
Guy-Bernier Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada.
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S
Brochu
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B
Rioux-Massé
J
J
Roy
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DC
Roy
C
C
Perreault
D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002454:Cell Differentiation; D019070:Cell Lineage; D053222:Fas Ligand Protein; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D011828:Radiation Chimera; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000637:transplantation; D013950:Thymus Gland / Q000166:cytology; D019172:Transplantation Conditioning; D019014:fas Receptor / Q000096:biosynthesis
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor