¹Institute for Immunobiology and Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence: Y Wang and S Xiong, Department of Immunology, Shanghai Medical College of Fudan University, 138 Yixueyuan Road, Shanghai, 200032, China. Tel: +86 21 54237324; Fax: +86 21 54237749; E-mail: yingwang2200@yahoo.com.cn or sdxiongfd@126.com

Received 11 December 2006; Revised 23 July 2007; Accepted 24 July 2007; Published online 31 August 2007.

Abstract

CD4⁺CD25⁺ regulatory T cells (Treg) are potent immunosuppressive cells active in controlling normal pathological immune responses. The mechanisms of this suppression have been investigated under various conditions. In this report, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)/death receptor 5 (DR5) was explored as one of the pivotal factors for the suppression and cytotoxicity induced by CD4⁺CD25⁺ Treg. Cell death was involved in the suppression induced by activated CD4⁺CD25⁺ Treg in vitro. The induction of CD4⁺ T cell death was not mediated by the CD95/CD95L pathway, but rather depended upon the upregulation of TRAIL in the Treg. Blocking the TRAIL/DR5 pathway resulted in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg in vitro. Activated Treg displayed TRAIL-dependent cytotoxicity against CD4⁺ T cells in vivo. The prolonged survival of allogeneic skin grafts induced by Treg was inhibited by DR5-blocking antibodies. Our findings suggest that the TRAIL/DR5 pathway is one of the mechanisms used by Treg to regulate immune responses both in vitro and in vivo.