Regulation of immunity during visceral Leishmania infection

Abstract

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.

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

Fig. 2

Dysfunctional humoral response during visceral leishmaniasis. The picture summarizes the sequence of events that lead to a suboptimal humoral response during visceral leishmaniasis, based primarily on data from our recent study in non-human primates compounded with evidence from additional studies. (1) Shortly after parasite inoculation, B cells are activated in a non-specific manner by soluble parasite products that act as B cell mitogens as well as by inflammatory mediators generated during the response to infection. (2) As a result, B cells with the atypical CD21⁻ CD27⁻ phenotype expand and eventually give rise to plasmablasts that produce copious amounts of immunoglobulin leading to the occurrence of hypergammaglobulinemia. (3) Some B cells appear to be activated in a specific manner via their BCR and follow the follicular pathway where they engage in cognate interactions with pre-Tfh cells. (4) If these interactions are productive, both cell types proceed to form a germinal center where Tfh cells promote affinity maturation of B cell for their specific antigen and direct the selection of the B cells clones with the highest affinity. B cells then exit the germinal center as high-affinity CD27+ memory B cells and plasma cells that produce antibodies with high affinity for the parasite. (5) However, the germinal center response is not sustained during the chronic phase of infection accompanying the decreasing numbers of Tfh cells. A strong Th1-polarizing environment is established in the spleen during VL, with high levels of expression of T-bet in CD4 T cells. Given that T-bet and the Tfh master transcription factor, Bcl-6, mutually repress each other’s expression, it is reasonable to speculate that the inflammatory environment during VL is unfavourable for the sustained differentiation of Tfh cells