Modulation of Innate Immune Mechanisms to Enhance Leishmania Vaccine-Induced Immunity: Role of Coinhibitory Molecules

Abstract

No licensed human vaccines are currently available against any parasitic disease including leishmaniasis. Several antileishmanial vaccine formulations have been tested in various animal models, including genetically modified live-attenuated parasite vaccines. Experimental infection studies have shown that Leishmania parasites utilize a broad range of strategies to undermine effector properties of host phagocytic cells, i.e., dendritic cells (DCs) and macrophages (MΦ). Furthermore, Leishmania parasites have evolved strategies to actively inhibit TH1 polarizing functions of DCs and to condition the infected MΦ toward anti-inflammatory/alternative/M2 phenotype. The altered phenotype of phagocytic cells is characterized by decreased production of antimicrobial reactive oxygen, nitrogen molecules, and pro-inflammatory cytokines, such as IFN-γ, IL-12, and TNF-α. These early events limit the activation of TH1-effector cells and set the stage for pathogenesis. Furthermore, this early control of innate immunity by the virulent parasites results in substantial alteration in the adaptive immunity characterized by reduced proliferation of CD4(+) and CD8(+) T cells and TH2-biased immunity that results in production of anti-inflammatory cytokines, such as TGF-β, and IL-10. More recent studies have also documented the induction of coinhibitory ligands, such as CTLA-4, PD-L1, CD200, and Tim-3, that induce exhaustion and/or non-proliferation in antigen-experienced T cells. Most of these studies focus on viral infections in chronic phase, thus limiting the direct application of these results to parasitic infections and much less to parasitic vaccines. However, these studies suggest that vaccine-induced protective immunity can be modulated using strategies that enhance the costimulation that might reduce the threshold necessary for T cell activation and conversely by strategies that reduce or block inhibitory molecules, such as PD-L1 and CD200. In this review, we will focus on the polarization of antigen-presenting cells and subsequent role of costimulatory and coinhibitory molecules in mediating vaccine-induced immunity using live-attenuated Leishmania parasites as specific examples.

Keywords: CD200; CD200R; CTLA-4; PD-L1; TIM-3; coinhibitory molecules; leishmaniasis; vaccine.

Figure 1

A schematic diagram describing the differential modulation of antigen-presenting cells in the early innate response and role of coinhibitory molecules in adaptive immunity in Leishmania pathogenesis is shown. (A) Virulent Leishmania donovani parasites are known to suppress antigen-presenting activity of DCs and macrophages. This is shown to be accompanied by reduction in the inflammatory cytokines as compared to infection with live-attenuated L. donovani parasites. These differences in the early interaction with the host APCs by the parasites determine the outcome, i.e., host susceptibility in case of virulent parasites or host resistance in case of attenuated parasites. (B) Previous studies have shown the role of coinhibitory molecules, such as CTLA-4, PD-L1, and CD200, in facilitating the parasite survival by inducing a restrained pro-inflammatory (T_H1) environment. The role of Tim-3 in Leishmania pathogenesis remains to be explored. The role of coinhibitory molecules in shaping the T cell immunity suggests that attenuated parasites might downregulate these pathways compared to virulent parasites in order to induce protective immunity. Blockade of the coinhibitory signals during priming by use of adjuvants might show potential improvement in the vaccine-induced immunity.