title: ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner.
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 CD4(hi) 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 CD4(hi) Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4(hi) Treg induced by allogeneic CD40-activated B cells. More importantly, CD4(hi) Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4(hi) 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 CD4(hi) Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4(hi) Treg and uncover a novel relationship between ICOS and CTLA-4.
authors: Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, PR China.
authors: Jian
authors: J
authors: Zheng
authors: Ping-Lung
authors: PL
authors: Chan
authors: Yinping
authors: Y
authors: Liu
authors: Gang
authors: G
authors: Qin
authors: Zheng
authors: Z
authors: Xiang
authors: Kwok-Tai
authors: KT
authors: Lam
authors: David B
authors: DB
authors: Lewis
authors: Yu-Lung
authors: YL
authors: Lau
authors: Wenwei
authors: W
authors: Tu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
chemical_list: D060908:CTLA-4 Antigen; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011993:Recombinant Fusion Proteins