Research Papers: Immunology:
Suppression of allograft rejection by CD8+CD122+PD-1+ Tregs is dictated by their Fas ligand-initiated killing of effector T cells versus Fas-mediated own apoptosis
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Abstract
Huazhen Liu1, Yeshu Wang2, Qiaohuang Zeng2, Yu-Qun Zeng2,3, Chun-Ling Liang1, Feifei Qiu1, Hong Nie4 and Zhenhua Dai1
1 Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, and Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, P.R. China
2 Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, P.R. China
3 Student Exchange Program, Mayo Clinic, Rochester, MN, USA
4 Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, Guangdong, P.R. China
Correspondence to:
Zhenhua Dai, email:
Keywords: transplantation, Treg, immunoregulation, T cell apoptosis, Immunology and Microbiology Section, Immune response, Immunity
Received: January 21, 2017 Accepted: February 13, 2017 Published: February 20, 2017
Abstract
Mounting evidence has shown that naturally occurring CD8+CD122+ T cells are regulatory T cells (Tregs) that suppress both autoimmunity and alloimmunity. We have previously shown that CD8+CD122+PD-1+ Tregs not only suppress allograft rejection, but also are more potent in suppression than conventional CD4+CD25+ Tregs. However, the mechanisms underlying their suppression of alloimmunity are not well understood. In an adoptive T-cell transfer model of mice lacking lymphocytes, we found that suppression of skin allograft rejection by CD8+CD122+PD-1+ Tregs was mostly dependent on their expression of Fas ligand as either lacking Fas ligand or blocking it with antibodies largely abolished their suppression of allograft rejection mediated by transferred T cells. Their suppression was also mostly reversed when effector T cells lacked Fas receptor. Indeed, these FasL+ Tregs induced T cell apoptosis in vitro in a Fas/FasL-dependent manner. However, their suppression of T cell proliferation in vitro was dependent on IL-10, but not FasL expression. Furthermore, adoptive transfer of CD8+CD122+PD-1+ Tregs significantly extended allograft survival even in wild-type mice if Tregs lacked Fas receptor or if recipients received recombinant IL-15, as these two measures synergistically expanded adoptively-transferred Tregs in recipients. Thus, this study may have important implications for Treg therapies in clinical transplantation.
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PII: 15551