title: Indoleamine 2,3-dioxygenase regulates T cell activity through Vav1/Rac pathway.
abstract: The immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) suppresses T-cell responses and promotes immune tolerance in tumor resistance. A previous study determined that IDO inhibits Vav1 mRNA expression and the activation of Vav1 and its downstream targets in T cells in the guanine exchange factor (GEF)-independent pathway. The current study aims to determine whether IDO induces T-cell immunosuppression through Vav1/Rac signaling pathway, which is a GEF-dependent pathway. The correlation between Vav1 mRNA expressions in T cells of tumor infiltrating lymphocytes and the levels of IDO expression in lung cancer tissues from lung cancer patients was detected. HEK293 cells were stably transfected with human IDO (HEK293-IDO). T cells were isolated from human blood. HEK293-IDO cells were co-incubated with T cells in the presence or absence of an anti-CD3 antibody to activate T cell receptor (TCR) and/or 1-methyl-l-tryptophan (1-MT) to inhibit IDO activity. The early signaling proteins in T-cytoskeleton regulation through Vav1/Rac pathway of T cell were determined. A significant and negative correlation was observed between IDO and Vav1 expression in the tumor microenvironment. IDO, which was produced by HEK293-IDO cells, significantly inhibited the expression of Vav1, which resulted in defective F-actin reorganization. Thus, TCR signaling initiation was damaged. The effects on T-cells induced by the co-culture of HEK293-IDO cells with T cells were attenuated by 1-MT. Results indicate that the inhibitory effects of IDO on T cell immune responses may occur through the down-regulation of Vav1 protein expression and the suppression of Vav1/Rac cascade. These studies provide insight into the mechanisms of immune escape induced by IDO.
authors.affiliation: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.
authors.forename: Runmei
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China. Electronic address: rwziyi@yahoo.com.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
mesh_terms: D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D018920:Coculture Techniques; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D016133:Polymerase Chain Reaction; D051567:Proto-Oncogene Proteins c-vav / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019139:Tumor Escape / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology; D020744:rac GTP-Binding Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D020744:rac GTP-Binding Proteins
keywords: F-actin; GEF; Indoleamine 2,3-dioxygenase (IDO); Rac; Vav1