Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease.
Fas ligand (FasL) and perforin pathways not only are the major mechanisms of T cell-mediated cytotoxicity but also are involved in homeostatic regulation of these T cells. In the present study, we tested whether CD8+ donor T cells that are deficient in both perforin and FasL (cytotoxic double deficient [cdd]) could induce graft-versus-host disease (GVHD) in a major histocompatibility complex class I-mismatched lethally irradiated murine model. Interestingly, recipients of cdd CD8+ T cells demonstrated significantly greater serum levels of interferon gamma and tumor necrosis factor alpha and histopathologic damage from GVHD than wild-type (wt) T cells on day 30 after allogeneic bone marrow transplantation (P<.05). Wt and either perforin-deficient or FasL-deficient CD8+ T cells expanded early after transplantation followed by a contraction phase in which the majority of expanded CD8+ T cells were eliminated. In contrast, cdd CD8+ T cells exhibited prolonged expansion and reduced apoptosis to alloantigen stimulation in vivo and in vitro. Together these results suggest that donor cdd CD8+ T cells expand continuously and cause lethal GVHD, and that both perforin and FasL are required for the contraction of allo-reactive CD8+ T cells.
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, 1500 East Medical Center Dr, Ann Arbor, MI 48109-0942, USA.
Yoshinobu
Y
Maeda
Robert B
RB
Levy
Pavan
P
Reddy
Chen
C
Liu
Shawn G
SG
Clouthier
Takanori
T
Teshima
James L M
JL
Ferrara
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018929:Cell Culture Techniques; D053222:Fas Ligand Protein; D006086:Graft vs Host Disease / Q000276:immunology*; D006648:Histocompatibility; D015395:Histocompatibility Antigens Class I; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014184:Transplantation, Homologous
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin