ICOS Regulates the Generation and Function of Human CD4+ Treg in a CTLA-4 Dependent Manner |
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Authors: | Jian Zheng Ping-Lung Chan Yinping Liu Gang Qin Zheng Xiang Kwok-Tai Lam David B Lewis Yu-Lung Lau Wenwei Tu |
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Institution: | 1. Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, PR China.; 2. Division of Immunology and Allergy, Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, United States of America.; Agency for Science, Technology and Research (A*STAR), Singapore, |
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Abstract: | Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4+ T cells and induced regulatory CD4+ T cells (CD4+ iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4hi Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4hi Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4hi Treg induced by allogeneic CD40-activated B cells. More importantly, CD4hi Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4hi Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4hi Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4hi Treg and uncover a novel relationship between ICOS and CTLA-4. |
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