In:
PLOS Pathogens, Public Library of Science (PLoS), Vol. 19, No. 5 ( 2023-5-12), p. e1011396-
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.
Type of Medium:
Online Resource
ISSN:
1553-7374
DOI:
10.1371/journal.ppat.1011396
DOI:
10.1371/journal.ppat.1011396.g001
DOI:
10.1371/journal.ppat.1011396.g002
DOI:
10.1371/journal.ppat.1011396.g003
DOI:
10.1371/journal.ppat.1011396.g004
DOI:
10.1371/journal.ppat.1011396.g005
DOI:
10.1371/journal.ppat.1011396.g006
DOI:
10.1371/journal.ppat.1011396.t001
DOI:
10.1371/journal.ppat.1011396.s001
DOI:
10.1371/journal.ppat.1011396.s002
DOI:
10.1371/journal.ppat.1011396.s003
DOI:
10.1371/journal.ppat.1011396.s004
DOI:
10.1371/journal.ppat.1011396.s005
DOI:
10.1371/journal.ppat.1011396.s006
DOI:
10.1371/journal.ppat.1011396.s007
DOI:
10.1371/journal.ppat.1011396.s008
DOI:
10.1371/journal.ppat.1011396.s009
DOI:
10.1371/journal.ppat.1011396.s010
DOI:
10.1371/journal.ppat.1011396.s011
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2205412-1
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