Upregulation of LAG3 modulates the immune imbalance of CD4+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model

Abstract

Infection with the cestode Echinococcus multilocularis (E. multilocularis) causes alveolar echinococcosis (AE), a tumor-like disease predominantly affecting the liver but able to spread to any organ. T cells develop functional defects during chronic E. multilocularis infection, mostly due to upregulation of inhibitory receptors such as T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and programmed death-1 (PD-1). However, the role of lymphocyte activation gene-3 (LAG3), an inhibitory receptor, in AE infection remains to be determined. Here, we discovered that high expression of LAG3 was mainly found in CD4+ T cells and induced regulatory T cells (iTregs) in close liver tissue (CLT) from AE patients. In a mouse model of E. multilocularis infection, LAG3 expression was predominantly found in T helper 2 (Th2) and Treg subsets, which secreted significantly more IL-4 and IL-10, resulting in host immune tolerance and disease progression at a late stage. Furthermore, LAG3 deficiency was found to drive the development of effector memory CD4+ T cells and enhance the type 1 CD4+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4+ T cells from LAG3-deficient mice produced more IFN-γ and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4+ T cells were more likely to develop into Th1 cells and less likely to develop into Tregs in recipient mice. Our work reveals that high expression of LAG3 accelerates AE disease progression by modulating the immune imbalance of CD4+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection.

Immunological Characteristics of Hepatic Dendritic Cells in Patients and Mouse Model with Liver Echinococcus multilocularis Infection

“…In recent years, accumulating evidence has shown that immune checkpoint molecules (LAG3, PD-1, and CTLA-4) are highly expressed in T cells and negatively regulate the function of T cells in immune responses [44,45]. Our recent research showed that the checkpoint molecules TIGIT and LAG3 are aberrantly expressed in T cells, leading to T cell exhaustion during E. multilocularis infection, thus accelerating disease progression [9,12].…”

“…In recent years, accumulating literature has focused on investigating T cell roles in AE pathogenesis, and impaired T cell responses have been reported, leading to liver immunosuppressive microenvironment formation and contributing to E. multilocularis chronic infection [8][9][10][11]. Mechanistically, infiltrating T cells in the hepatic AE lesion microenvironment exhibit high and sustained expression of immune checkpoint receptors, such as lymphocyte activation gene-3 (LAG3), programmed cell death-1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and 2B4 (CD244), which mediate E. multilocularis immune escape by impairing T cell functions [9,12]. Dendritic cells (DCs) are highly heterogeneous cell populations, and different DC populations exhibit different phenotypes and functions [13].…”

Plasma proteomics analysis of Chinese HIV-1 infected individuals focusing on the immune and inflammatory factors afford insight into the viral control mechanism

“…As a confirmed immune checkpoint, LAG3 is mainly expressed in immune cells such as activated T cells, regulatory T cells (Treg cells) and natural killer cells (NK cells) (27). The primary function of LAG3 is to inhibit T-cell activation and function, resulting in T-cell exhaustion via binding to MHC-II (24,25). The high expression of LAG3 in VPs was also accompanied by the low CD4 + T-cell count and high viral load, which mutually proved immune exhaustion and uncontrolled viral replication.…”

“…The high expression of LAG3 in VPs was also accompanied by the low CD4 + T-cell count and high viral load, which mutually proved immune exhaustion and uncontrolled viral replication. Also, LAG3 deficiency in mice had been found to drive the development of effector memory CD4 + T-cell and enhance CD4 + Th-1 cell immune responses, thus reversing the trend of T cell exhaustion (25). Therefore, ART in combination with immune checkpoint inhibitors may provide a new idea for HIV treatment.…”

“…Briefly, nine DEPs were identified between LTNPs and VPs, which included four immune factors (NF2, DAPP1, DDX58 and FAM3B) and five inflammatory factors (SIRT2, IL-17C, CCL25, IL-10 and TWEAK). Moreover, a well-known immune checkpoint factor, LAG3, which is associated with immune exhaustion (24,25), was differentially expressed in LTNPs vs. VPs, LTNPs vs. TPs, VPs vs. TPs, and VPs vs. HCs, respectively. In addition, the expression level of LAG3 in VPs was the highest among the four groups.…”