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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2023-2027.
Prepublished online as a Blood First Edition Paper on October 5, 2004; DOI 10.1182/blood-2004-08-3036.
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Submitted August 5, 2004
Accepted September 22, 2004
Both perforin and Fas ligand are required for the regulation of alloreactive CD8+ T cells during acute graft-versus-host disease
Yoshinobu Maeda, Robert B Levy, Pavan Reddy, Chen Liu, Shawn G Clouthier, Takanori Teshima, and James L Ferrara*
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL, USA
Department of Pathology, University of Florida College of Medicine, Gainesville, FL, USA
Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; Department of Pediatrics, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA
* Corresponding author; email: ferrara{at}umich.edu.
Fas ligand (FasL) and perforin pathways are not only the major mechanisms of T cell-mediated cytotoxicity but are also 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 (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<0.05). 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 alloreactive CD8+ T cells.
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