The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects

• Published in: The Journal of immunology (1950) Vol. 194; no. 8; pp. 3873 - 3882
• Main Authors: Tian, Xiaoling, Zhang, Anli, Qiu, Chao, Wang, Wei, Yang, Yu, Qiu, Chenli, Liu, Aiping, Zhu, Lingyan, Yuan, Songhua, Hu, Huiliang, Wang, Wanhai, Wei, Qiang, Zhang, Xiaoyan, Xu, Jianqing
• Format: Journal Article
• Language: English
• Published: United States 15.04.2015
• Subjects: Adult; Animals; Antigens, CD - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Disease Progression; Female; Gene Expression Regulation - immunology; Histocompatibility Antigens Class II - immunology; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - pathology; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Macaca mulatta; Male; Middle Aged; Programmed Cell Death 1 Receptor - immunology
• DOI: 10.4049/jimmunol.1402176
• ISSN: 0022-1767; 1550-6606

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.