DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease.

Abstract:

:CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft-versus-host disease (GVHD) in murine models of allogeneic hematopoietic stem cell transplantation. We recently demonstrated that a single treatment of the agonistic antibody to DR3 (death receptor 3, αDR3) to donor mice resulted in the expansion of donor-derived Treg and prevented acute GVHD, although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3-activated Treg (DR3-Treg) had an activated/mature phenotype. Furthermore, the CD25+Foxp3+ subpopulation in DR3-Treg showed stronger suppressive effects in vivo. Prophylactic treatment of αDR3 to recipient mice expanded recipient-derived Treg and reduced the severity of GVHD, whereas DR3 activation in mice with ongoing GVHD further promoted donor T-cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. In conclusion, our data demonstrated that DR3 signaling affects the function of Treg and T-cell activation after alloantigen exposure in a time-dependent manner. These observations provide important information for future clinical testing using human DR3 signal modulation and highlight the critical effect of the state of T-cell activation on clinical outcomes after activation of DR3.

journal_name

Blood

journal_title

Blood

authors

Nishikii H,Kim BS,Yokoyama Y,Chen Y,Baker J,Pierini A,Alvarez M,Mavers M,Maas-Bauer K,Pan Y,Chiba S,Negrin RS

doi

10.1182/blood-2016-06-723783

subject

Has Abstract

pub_date

2016-12-15 00:00:00

pages

2846-2858

issue

24

eissn

0006-4971

issn

1528-0020

pii

blood-2016-06-723783

journal_volume

128

pub_type

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