A Schistosoma japonicum Infection Promotes the Expansion of Myeloid-Derived Suppressor Cells by Activating the JAK/STAT3 Pathway.

Myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immune cells from the myeloid lineage, play an important part in suppression of host immune responses during many pathologic conditions, including cancer and infectious diseases. Thus, understanding the functional diversity of these cells as well as the underlying mechanisms is crucial for the development of disease control strategies. The role of MDSCs during Schistosoma japonicum infection, however, is not clear, and there is a lack of systematic study so far. In this study, we provide strong evidence that the soluble egg Ag (SEA) and schistosome worm Ag (SWA) of S. japonicum enhance the accumulation of MDSCs. Ag-induced MDSCs have more potent suppressive effects on T cell responses than do control MDSCs in both in vivo S. japonicum infection and in vitro SEA- and SWA-treated mouse bone marrow cells experiments. Interestingly, the enhanced suppressive activity of MDSCs by Ag administration was coupled with a dramatic induction of the NADPH oxidase subunits gp91phox and p47phox and was dependent on the production of reactive oxygen species. Moreover, mechanistic studies revealed that the Ag effects are mediated by JAK/STAT3 signaling. Inhibition of STAT3 phosphorylation by the JAK inhibitor JSI-124 almost completely abolished the Ag effects on the MDSCs. In summary, this study sheds new light on the immune modulatory role of SEA and SWA and demonstrates that the expansion of MDSCs may be an important element of a cellular network regulating immune responses during S. japonicum infection.

Differential pulmonic NK and NKT cell responses in Schistosoma japonicum-infected mice.

Natural killer cells (NK cells) and natural killer T cells (NKT cells) play a role in anti-infection, anti-tumor, transplantation immunity, and autoimmune regulation. However, the role of NK and NKT cells during Schistosoma japonicum (S. japonicum) infection has not been widely reported, especially regarding lung infections. The aim of this study was to research the NK and NKT cell response to S. japonicum infection in the lungs of mice. Using immunofluorescent histological analysis, NK and NKT cells were found near pulmonary granulomas. Moreover, flow cytometry revealed that the percentage and number of pulmonic NK cells in S. japonicum-infected mice were significantly increased (P < 0.05). However, the percentage and cell number of NKT cells were decreased compared to those of normal mice (P < 0.05). The expression of CD69 on pulmonic NK and NKT cells was increased after infection (P < 0.05), and CD25 expression increased only on NKT cells (P < 0.05). Intracellular cytokine staining showed a higher percentage of IFN-γ+ and lower percentage of IL-5+ pulmonic NK cells (P < 0.05) compared to controls. However, the percentage of IL-17+, IL-10+, and IL-5+ pulmonic NKT cells significantly increased (P < 0.05). Additionally, there was a significant decrease in NKG2A/C/E (CD94) expression and an increase of NKG2D (CD314) expression on pulmonic NKT cells (P < 0.05), which might serve as a mechanism for NKT cell activation during S. japonicum infection.

Characteristics of Schistosoma japonicum infection induced IFN-γ and IL-4 co-expressing plasticity Th cells.

Schistosoma japonicum infection can induce granulomatous inflammation and cause tissue damage in the mouse liver. The cytokine secretion profile of T helper (Th) cells depends on both the nature of the activating stimulus and the local microenvironment (e.g. cytokines and other soluble factors). In the present study, we found an accumulation of large numbers of IFN-γ(+)  IL-4(+)  CD4(+) T cells in mouse livers. This IFN-γ(+)  IL-4(+) cell population increased from 0·68 ± 0·57% in uninfected mice to 7·05 ± 3·0% by week 4 following infection and to 9·6 ± 5·28% by week 6, before decreasing to 6·3 ± 5·9% by week 8 in CD4 T cells. Moreover, IFN-γ(+)  IL-4(+) Th cells were also found in mouse spleen and mesenteric lymph nodes 6 weeks after infection. The majority of the IFN-γ(+)  IL-4(+) Th cells were thought to be related to a state of immune activation, and some were memory T cells. Moreover, we found that these S. japonicum infection-induced IFN-γ(+)  IL-4(+) cells could express interleukin-2 (IL-2), IL-9, IL-17 and high IL-10 levels at 6 weeks after S. japonicum infection. Taken together, our data suggest the existence of a population of IFN-γ(+)  IL-4(+) plasticity effector/memory Th cells following S. japonicum infection in C57BL/6 mice.

The characteristics of NK cells in Schistosoma japonicum-infected mouse spleens.

Natural killer (NK) cells are classic innate immune cells that play roles in many types of infectious disease. Recently, some new characteristics of NK cells were discovered. In this study, C57BL/6 mice were infected with Schistosoma japonicum for 5-6 weeks and lymphocytes were isolated from the spleen to detect some of the NK cell characteristics by multiparametric flow cytometry. The results revealed that the S. japonicum infection induced a large amount of NK cells, although the percentage of NK cells was not increased significantly. At the same time, the results showed that infected mouse splenic NK cells expressed increased levels of CD25 and CD69 and produced more IL-2, IL-4, and IL-17 and less IFN-γ after stimulation with PMA and ionomycin. This meant that NK cells played a role in S. japonicum infection. Moreover, decreased NKG2A/C/E (CD94) expression levels were detected on the surface of NK cells from infected mouse spleens, which might serve as a NK cell activation mechanism. Additionally, high levels of IL-10, but not PD-1, were expressed on the infected mouse NK cells, which implied that functional exhaustion might exist in the splenic NK cells from S. japonicum-infected mice. Collectively, our results suggest that NK cells play important roles in the course of S. japonicum infection.

Adjustments of γδ T Cells in the Lung of Schistosoma japonicum-Infected C56BL/6 Mice.

Many kinds of lymphocytes are involved in Schistosoma japonicum (S. japonicum) infection-induced disease. γδ T cells comprise a small number of innate lymphocytes that quickly respond to foreign materials. In this study, the role of γδ T cells in the lung of S. japonicum-infected C56BL/6 mice was investigated. The results demonstrated that S. japonicum infection induces γδ T cell accumulation in the lung, expressing higher levels of CD25, MHCII, CD80, and PDL1, and lower levels of CD127 and CD62L (P < 0.05). The intracellular cytokines staining results illustrated higher percentages of IL-4-, IL-10-, IL-21-, and IL-6-producing γδ T cells and lower percentages of IFN-γ-expressing γδ T cells in the lung of infected mice (P < 0.05). Moreover, the granuloma size in lung tissue was significantly increased in Vδ-/- mice (P < 0.05). In the lung of S. japonicum-infected Vδ-/- mice, both type 1 and type 2 immune responses were decreased significantly (P < 0.05). In addition, the expression of CD80 and CD69 on B cells was decreased significantly (P < 0.05), and the SEA-specific antibody was markedly decreased (P < 0.05) in the blood of infected Vδ-/- mice. In conclusion, this study indicates that γδ T cells could adjust the Th2 dominant immune response in the lung of S. japonicum-infected mice.

Characteristics of IL-9 induced by Schistosoma japonicum infection in C57BL/6 mouse liver.

Liver granulomatous inflammation and fibrosis were the primary pathological changes observed during Schistosoma japonicum (S. japonicum) infection. In the present study, the characteristics of IL-9 were investigated in the liver of S. japonicum infection C57BL/6 mice. Immunofluorescence, qRT-PCR, and ELISA results demonstrated that the expression of IL-9 significantly increased after infection (P < 0.01). FACS results indicated that the peak of IL-9+ Th9 cells in the liver mononuclear cells appeared at the early phase of infection (week 5), except that Th9 cells, CD8+ Tc cells, NKT and γδT cells could secrete IL-9 in this model. Although IL-9 neutralization has a limited effect on liver granulomatous inflammation, it could decrease the level of fibrosis-associated factor, PC-III, in the serum of infected mice (P < 0.05). Taken together, our results indicated that IL-9 was an important type of cytokine involved in the progression of S. japonicum infection-induced hepatic damage.