Indoleamine 2,3-dioxygenase 1 signaling orchestrates immune tolerance in Echinococcus multilocularis-infected mice

Abstract

The cestode Echinococcus multilocularis larva infection causes lethal zoonotic alveolar echinococcosis (AE), a disease posing a great threat to the public health worldwide. This persistent hepatic tumor-like disease in AE patients has been largely attributed to aberrant T cell responses, of which Th1 responses are impeded, whilst Th2 and regulatory T cell responses are elevated, creating an immune tolerogenic microenvironment in the liver. However, the immune tolerance mechanisms are not fully understood. Dendritic cells (DCs) are key cellular components in facilitating immune tolerance in chronic diseases, including AE. Here, we demonstrate that indoleamine 2,3-dioxygenase 1-deficient (IDO1-/-) mice display less severe AE as compared to wild-type (WT) mice during the infection. Mechanistically, IDO1 prevents optimal T cells responses by programming DCs into a tolerogenic state. Specifically, IDO1 prevents the maturation and migration potential of DCs, as shown by the significantly enhanced expression of the antigen-presenting molecule (MHC II), costimulatory molecules (CD80 and CD86), and chemokine receptors (CXCR4 and CCR7) in infected IDO1-/- mice as compared to infected wild-type mice. More importantly, the tolerogenic phenotype of DCs is partly reverted in IDO1-/- mice, as indicated by enhanced activation, proliferation, and differentiation of both CD4+ and CD8+ - T cells upon infection with Echinococcus multilocularis, in comparison with WT mice. Interestingly, in absence of IDO1, CD4+ T cells are prone to differentiate to effector memory cells (CD44+CD62L-); in contrast, CD8+ T cells are highly biased to the central memory phenotype (CD44+CD62L+). Overall, these data are the first to demonstrate the essential role of IDO1 signaling in inducing immunosuppression in mice infected with Echinococcus multilocularis.

The expression of CTLA-4 in hepatic alveolar echinococcosis patients and blocking CTLA-4 to reverse T cell exhaustion in Echinococcus multilocularis-infected mice

“…Splenocytes were purified by referring to the previous method ( 25 ). The mice not infected with E. multilocularis were sacrificed, and the spleens were separated in a clean bench, washed with pre-cooled physiological saline, then cut into small pieces, and mechanically dispersed by using a sterile syringe plunger to force through a 70-μm cell strainer to obtain splenocytes.…”

Naringin ameliorates liver fibrosis in zebrafish by modulating IDO1-mediated lipid metabolism and inflammatory infiltration

“…Previous research underscores the paramount significance of hepatocyte-expressed IDO1 in fostering the immunological tolerance of the liver. 42 IDO1 is expressed by many cell types, especially macrophages. 43 IDO1 can affect the progression of fibrosis in the liver.…”

Modulation of the Indolamine 2,3 Dioxygenase Pathway as a Means of Treating Depression

“…Numerous studies have demonstrated that IDO is expressed by cancer cells themselves as well as by cells surrounding the tumor including macrophages, myeloid derived suppressor cells and even fibroblasts [48]. IDO is also found in other states of immune evasion such as in the tuberculosis granuloma [49], in parasitic infections [50], and in testicular immune privilege [51].…”