Fig. 1

The immunologic environment in the spleen during visceral leishmaniasis. The picture aims to summarize the main host-protective responses occurring during VL in the spleen, as well as the major immune networks that promote parasite persistence (top half). Protective responses in the spleen are initiated by DCs exposed to parasite products, but not productively infected by Leishmania (bystander DCs). These secrete cytokines such as IL-12 or IL-23 that guide the differentiation of Th1 or Th17 cells, respectively, which, in turn, will produce IFNγ, TNF or IL-17 that maximize the capacity of infected macrophages to produce NO and ROS. In parallel, naïve CD8 T cells are primed by DCs in the presence of IL-12 and type I IFNs and differentiate into effector cells that further contribute to the protective response by producing IFNγ and TNF. Effector CD8 T cells may also degranulate perforin and granzymes and kill infected cells, although it remains unclear whether cytotoxic mediators play any protective role during VL. In contrast, in infected DCs the parasite hijacks the capacity of the cell to initiate protective responses (the mechanisms employed by Leishmania to subvert signaling pathways and impair host cell function fall outside the scope of this review and the reader is referred to recent reviews [167, 168]). The combined secretion of cytokines such as IL-12, IL-27 and IL10 by infected DCs leads to the differentiation of Tr1 cells that simultaneously produce IFN-γ and IL-10 and decrease the leishmanicidal capacity of the macrophage. In parallel, parasite persistence and possibly suppressive cytokines lead to the exhaustion of specific CD8 T cells, by upregulating the expression of inhibitory receptors such as PD-1, LAG-3 or additional unidentified receptors. These cells perform very limited effector function hence decreasing the capacity of the host to fight the parasite