Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease.
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.
Zeiser
Robert
R
Division of Bone Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, CA 94305, USA.
Nguyen
Vu H
VH
Hou
Jing-Zhou
JZ
Beilhack
Andreas
A
Zambricki
Elizabeth
E
Buess
Martin
M
Contag
Christopher H
CH
Negrin
Robert S
RS
D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D053285:CD30 Ligand / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D007519:Isoantigens / Q000276:immunology; D017730:Ki-1 Antigen / Q000276:immunology*; D051379:Mice; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D053285:CD30 Ligand; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; D017730:Ki-1 Antigen