title: The upregulation of LAG-3 on T cells defines a subpopulation with functional exhaustion and correlates with disease progression in HIV-infected subjects.
abstract: T cells develop functional defects during HIV-1 infection, partially due to the upregulation of inhibitory receptors such as programmed death-1 (PD-1) and CTLA-4. However, the role of lymphocyte activation gene-3 (LAG-3; CD223), also known as an inhibitory receptor, in HIV infection remains to be determined. In this study, we revealed that LAG-3 on T cells delivers an inhibitory signal to downregulate T cell functionality, thereby playing an immunoregulatory role during persistent HIV-1 infection. We observed that HIV-1 infection results in a significant increase in LAG-3 expression in both the peripheral blood and the lymph nodes. The upregulation of LAG-3 is dramatically manifested on both CD4(+) and CD8(+) T cells and is correlated with disease progression. As expected, prolonged antiretroviral therapy reduces the expression of LAG-3 on both CD4(+) and CD8(+) T cells. The ex vivo blockade of LAG-3 significantly augments HIV-specific CD4(+) and CD8(+) T cell responses, whereas the overexpression of LAG-3 in T cells or the stimulation of LAG-3 on T cells leads to the reduction of T cell responses. Furthermore, most LAG-3 and PD-1 are expressed in different T cell subsets. Taken together, these data demonstrate that the LAG-3/MHC class II pathway plays an immunoregulatory role, thereby providing an important target for enhancing immune reconstitution in HIV-infected patients. Additionally, the LAG-3/MHC class II pathway may synergize with PD-1/PD ligand to enhance T cell-mediated immune responses.
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Tian
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Anli
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Chao
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100021, China; and.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Chenli
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Aiping
authors.initials: A
authors.lastname: Liu
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Songhua
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Huiliang
authors.initials: H
authors.lastname: Hu
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China;
authors.forename: Wanhai
authors.initials: W
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100021, China; and.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China; State Key Laboratory for Infectious Disease Prevention and Control, Chinese Center for Disease Control and Prevention, Beijing 102206, China xujianqing2014@126.com zhangxiaoyan@shaphc.org.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, Shanghai 201508, China; State Key Laboratory for Infectious Disease Prevention and Control, Chinese Center for Disease Control and Prevention, Beijing 102206, China xujianqing2014@126.com zhangxiaoyan@shaphc.org.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Xu
mesh_terms: D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein