학술논문
Upregulation of LAG3 modulates the immune imbalance of CD4.sup.+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model
Research Article
Research Article
Document Type
Report
Author
Source
PLoS Pathogens. May 12, 2023, Vol. 19 Issue 5, e1011396
Subject
Language
English
ISSN
1553-7366
Abstract
Author(s): Dewei Li 1,2, Abidan Ainiwaer 1,2, Xuran Zheng 1,2, Maolin Wang 1,2, Yang Shi 1,2, Zibigu Rousu 1,2, Xinling Hou 1,2, Xuejiao Kang 1,2, Muesier Maimaiti 1,2, Hui Wang [...]
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.sup.+ 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.sup.+ T cells and enhance the type 1 CD4.sup.+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4.sup.+ T cells from LAG3-deficient mice produced more IFN-[gamma] and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4.sup.+ 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.sup.+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection.
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.sup.+ 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.sup.+ T cells and enhance the type 1 CD4.sup.+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4.sup.+ T cells from LAG3-deficient mice produced more IFN-[gamma] and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4.sup.+ 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.sup.+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection.