Plasmodium yoelii Infection Enhances the Expansion of Myeloid-Derived Suppressor Cells via JAK/STAT3 Pathway.

Myeloid-derived suppressor cells (MDSCs), the negative immune regulators, have been demonstrated to be involved in immune responses to a variety of pathological conditions, such as tumors, chronic inflammation, and infectious diseases. However, the roles and mechanisms underlying the expansion of MDSCs in malaria remain unclear. In this study, the phenotypic and functional characteristics of splenic MDSCs during Plasmodium yoelii NSM infection are described. Furthermore, we provide compelling evidence that the sera from P. yoelii-infected C57BL/6 mice containing excess IL-6 and granulocyte-macrophage colony-stimulating factor promote the accumulation of MDSCs by inducing Bcl2 expression. Serum-induced MDSCs exert more potent suppressive effects on T cell responses than control MDSCs within both in vivo P. yoelii infection and in vitro serum-treated bone marrow cells experiments. Serum treatment increases the MDSC inhibitory effect, which is dependent on Arg1 expression. Moreover, mechanistic studies reveal that the serum effects are mediated by JAK/STAT3 signaling. By inhibiting STAT3 phosphorylation with the JAK inhibitor JSI-124, effects of serum on MDSCs are almost eliminated. In vivo depletion of MDSCs with anti-Gr-1 or 5-fluorouracil significantly reduces the parasitemia and promotes Th1 immune response in P. yoelii-infected C57BL/6 mice by upregulating IFN-γ expression. In summary, this study indicates that P. yoelii infection facilitates the accumulation and function of MDSCs by upregulating the expression of Bcl2 and Arg1 via JAK/STAT3 signaling pathway in vivo and in vitro. Manipulating the JAK/STAT3 signaling pathway or depleting MDSCs could be promising therapeutic interventions to treat malaria.

TLR7 enhancing follicular helper T (Tfh) cells response in C57BL/6 mice infected with Plasmodium yoelii NSM TLR7 mediated Tfh cells in P. yoelii infected mice.

Toll-like receptors (TLRs) play an important role in inducing innate and acquired immune responses against infection. However, the effect of Toll-like receptor 7 (TLR7) on follicular helper T (Tfh) cells in mice infected with Plasmodium is still not clear. The results showed that the splenic CD4+ CXCR5+ PD-1+ Tfh cells were accumulated after Plasmodium yoelii NSM infection, the content of splenic Tfh cells was correlated to parasitemia and/or the red blood cells (RBCs) counts in the blood. Moreover, the expression of TLR7 was found higher than TLR2, TLR3 and TLR4 in splenic Tfh cells of the WT mice. TLR7 agonist R848 and the lysate of red blood cells of infected mice (iRBCs) could induce the activation and differentiation of splenic Tfh cells. Knockout of TLR7 leads to a decrease in the proportion of Tfh cells, down-regulated expression of functional molecules CD40L, IFN-γ, IL-21 and IL-10 in Tfh cells; decreased the proportion of plasma cells and antibody production and reduces the expression of STAT3 and Ikzf2 in Tfh cells. Administration of R848 could inhibit parasitemia, enhance splenic Tfh cell activation and increase STAT3 and Ikzf2 expression in Tfh cells. In summary, this study shows that TLR7 could regulate the function of Tfh cells, affecting the immune response in the spleen of Plasmodium yoelii NSM-infected mice.

TLR7 controls myeloid-derived suppressor cells expansion and function in the lung of C57BL6 mice infected with Schistosoma japonicum.

Toll-like receptors (TLRs) play an important role in the induction of innate and adaptive immune responses against Schistosoma japonicum (S. japonicum) infection. However, the role of Toll-like receptor 7 (TLR7) in the mouse lung during S. japonicum infection and the myeloid-derived suppressor cells (MDSCs) affected by the absence of TLR7 are not clearly understood. In this study, the results indicated that the MDSCs were accumulated and the proportion and activation of CD4+ and CD8+ T cells were decreased in the lung of mice at 6-7 weeks after S. japonicum infection. Then, the expression of TLR7 was detected in isolated pulmonary MDSCs and the results showed that the expression of TLR7 in MDSCs was increased after infection. Furthermore, TLR7 agonist R848 could down-regulate the induction effect of the soluble egg antigen (SEA) on pulmonary MDSCs in vitro. Meanwhile, TLR7 deficiency could promote the pulmonary MDSCs expansion and function by up-regulating the expression of PD-L1/2 and secreting of IL-10 in the mice infected with S. japonicum. Mechanistic studies revealed that S. japonicum infection and the antigen effects are mediated by NF-κB signaling. Moreover, TLR7 deficiency aggravates S. japonicum infection-induced damage in the lung, with more inflammatory cells infiltration, interstitial dilatation and granuloma in the tissue. In summary, this study indicated that TLR7 signaling inhibits the accumulation and function of MDSCs in S. japonicum infected mouse lung by down-regulating the expression of PD-L1/2 and secreting of IL-10, via NF-κB signaling.