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.

HIV-specific CD8+ T cells and HIV eradication

“…This is followed at late stages by apoptosis of HIV-specific CD8 + T cells (48). This exhausted state is associated with the upregulation of multiple activation and coinhibitory molecules (see below) (49)(50)(51)(52)(53)(54)(55). Several studies have demonstrated that prolonged ARV therapy results in some restoration of polyfunctionality and at least partial downregulation of activation and exhaustion markers (49)(50)(51)(52)(56)(57)(58)(59)(60).…”

“…Coinhibitory receptors, including PD-1, TIM-3, CD160, 2B4, LAG-3, and CTLA-4, play a critical role in the maintenance of exhaustion (49)(50)(51)(52)(53)(54)(55). Blockade of these receptorseither alone or in combination -has enhanced T cell function in vitro and viral control in multiple animal models (49)(50)(51)(52)(53)(54)(55)(129)(130)(131)(132), providing a rationale for testing coinhibitory pathway blockade as an immunotherapeutic strategy in HIV infection. Additional enthusiasm for this approach can be drawn from advances in cancer immunotherapy, in which Abs that block the PD-1 and CTLA-4 pathways have been highly successful and are considered breakthrough drugs in the treatment of solid tumors (133).…”

“…HIV-specific CD8 + T cell efficacy is partly limited by the effects of chronic immune stimulation on CD8 + T cell function. A variety of coinhibitory molecules, including programmed death 1 (PD-1), T cell Ig and mucin domain 3 (TIM-3), CD160, the NK cell receptor 2B4, lymphocyte activation gene 3 (LAG-3), and cytotoxic T lymphocyte antigen 4 (CTLA-4), which impair the antiviral function of HIV-specific CD8 + T cells that negatively regulate immune function, are expressed under conditions of chronic antigenic stimulation (49)(50)(51)(52)(53)(54)(55). Simultaneous expression of multiple coinhibitory molecules may result in even more profound functional immune impairment (71).…”

MicroRNA miR-126-5p Enhances the Inflammatory Responses of Monocytes to Lipopolysaccharide Stimulation by Suppressing Cylindromatosis in Chronic HIV-1 Infection

“…The basic characteristics of the studied subjects have been previously published (13,71). All of the HIV-1 patients were infected by blood transmissions during 1995 or 1996 and were enrolled in the study and have been followed up six times per year since 2009.…”

“…All of the HIV-1 patients were infected by blood transmissions during 1995 or 1996 and were enrolled in the study and have been followed up six times per year since 2009. For this study, 15 out of 37 ART-naive (ART Ϫ ) patients and 12 out of 19 ART-treated (ART ϩ ) patients were randomly selected based on the classification described in previous research (13,14,71). HIV-1-seronegative subjects were recruited from the Shanghai Public Health Clinical Center as healthy controls.…”