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Blood, 1 March 2007, Vol. 109, No. 5, pp. 2225-2233.
Prepublished online as a Blood First Edition Paper on October 26, 2006; DOI 10.1182/blood-2006-07-038455.
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TRANSPLANTATION
Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease
Robert Zeiser1,
Vu H. Nguyen1,
Jing-Zhou Hou1,
Andreas Beilhack1,
Elizabeth Zambricki1,
Martin Buess2,
Christopher H. Contag3, and
Robert S. Negrin1
1 Division of Bone Marrow Transplantation, Department of Medicine,
2 Division of Biochemistry, Department of Medicine,
3 Departments of Pediatrics, Radiology and Microbiology, and Immunology, Stanford University School of Medicine, CA
Murine CD4+CD25+ regulatory T cells (Treg cells) reduce acute graft-versus-host disease (aGvHD). However, surface molecules critical for suppression are unclear. Deficiency of CD30 (CD30–/–) leads to impaired thymic negative selection and augmented T-cell autoreactivity. Therefore, we investigated the role of CD30 signaling in Treg-cell function during aGvHD. Treg cells derived from CD30–/– animals were significantly less effective in preventing aGvHD lethality. Early blockade of the CD30/CD153 pathway with a neutralizing anti-CD153 mAb reduced Treg-mediated protection from proinflammatory cytokine accumulation and donor-type T-cell apoptosis. In vivo bioluminescence imaging demonstrated intact homing but reduced expansion of luciferase-expressing Treg cells when CD153 was blocked during the early phase after adoptive transfer. CD30 surface expression on Treg cells increased with alloantigen exposure, and CD153 expression on recipient-type dendritic cells increased in the presence of a proinflammatory environment. These data demonstrate that early CD30 signaling is critical for Treg-mediated aGvHD protection after major MHC-mismatch bone marrow transplantation.
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