Figure 5.

IL-27 tips the balance of immunity toward L. donovani survival. (A) L. donovani amastigotes invade hepatic macrophages (Kupffer cells). This event is followed by the invasion of leukocytes, neutrophils, monocytes, and T cells under the influence of chemotactic factors like CCL3, CCL2, and CXCL3 secreted by infected Kupffer cells. (B) These immunological reactions lead to the formation of a granuloma that is abundant in pro-inflammatory factors (IFN-γ, TNF-α, and RNI/ROS secreted by Th1 cells, NK cells, and CD8⁺ T cells); under such conditions L. donovani infection is resolved over time. (C) However, the abundance of IL-4 and IL-10 decreased iNOS expression, high production of IgG1/IgG2a ratio, and delayed maturation of granuloma, depletion of neutrophils results in high parasite load. (D) Elevated IL-10 secreted by Treg cells also contributes to L. donovani survival. (E) Splenic CD11c^hi MHC-II^hi DCs from L. donovani-infected C57BL/6 mice show high levels of IL-27. Similarly, L. donovani infection in BALB/c mice produces IL-27. In this case, CD8α⁺ and CD4⁺ DCs are the major producers. (F) In WSX-1^−/− C57BL/6 mice, a potent Th1 cell-linked response exhibits a severe hepatic inflammation (showing necrosis and deposition of reticulin fiber and collagen) that eventually resolves. In this context, IL-27-linked signals may suppress the Th1 response directly or indirectly, which helps in the suppression of hepatic inflammation by modulating the function of CD4⁺ T cells. (G) IL-27 supports the IL-10 production by IFN-γ producing Th1 cells in a pathway that involves the induction of STAT-1, STAT-3, and NOTCH signaling. (H) The generation of CD4⁺ IL-10⁺ T cells by IL-27 requires the expression of c-Maf, ICOS, and IL-21. (I) IL-27 also alters methylation patterns in the IL-10-gene promoter in CD4⁺ T cells that increase IL-10 expression directly. (J) IL-27, along with IL-21, enhances the differentiation of IL-10 producing TR1 cells during VL.