Leishmania-Infected MHC Class IIhigh Dendritic Cells Polarize CD4+ T Cells toward a Nonprotective T-bet+ IFN-γ+ IL-10+ Phenotype

Abstract

A differential behavior among infected and bystander dendritic cells (DCs) has been explored in different infection models. We have analyzed both populations sorted on contact with visceral Leishmania infantum on a susceptible mice model evaluating the subsequent repercussions on adaptive immune response. Our results demonstrate a clear dichotomy between the immunomodulatory abilities of bystander and infected DCs. The bystander population presents increased levels of IL-12p40 and costimulatory molecules being capable to induce CD4+ T cell activation with immune protective capabilities. In contrast, infected DCs, which express lower costimulatory molecules and higher levels of IL-10, promote the development of Leishmania Ag-specific, nonprotective T-bet+IFN-γ+IL-10+ CD4+ T cells with an effector phenotype. This specific polarization was found to be dependent on IL-12p70. Splenic infected DCs recovered from chronic infected animals are similarly capable to polarize ex vivo syngeneic naive CD4+ T cells toward a T-bet+IFN-γ+IL-10+ phenotype. Further analysis revealed that only MHC class IIhigh–infected DCs were responsible for this polarization. The adoptive transfer of such polarized CD4+ T cells facilitates visceral leishmaniasis in BALB/c mice in a clear contrast with their counterpart generated with bystander DCs that significantly potentiate protection. Further, we demonstrated that CD4+ T cells primed by infected DCs in an IL-10 free system, thus deprived of T-bet+IFN-γ+IL-10+ population, restore the immune response and reduce parasite load, supporting a deleterious role of IFN-γ+IL-10+ T cells in the maintenance of infection. Overall, our results highlight novel subversion mechanisms by which nonprotective T-bet+IFN-γ+IL-10+ T cells are associated with chronicity and prolonged parasite persistence.

Characterisation of the ex vivo virulence of Leishmania infantum isolates from Phlebotomus perniciosus from an outbreak of human leishmaniosis in Madrid, Spain

“…Leishmania infection induced lower amounts of IL-12p40 production compared to amounts observed when cells were stimulated with only LPS (Figure 3A), which is consistent with previous research [36]. Interestingly, the production of IL-12p40 was decreased mainly in BOS1FL1- and POL2FL7-infected BMMø and BMDC ( P <0.05), compared to amounts observed during infection with the BCN150 strain (Figure 3A).…”

Low CD40 Expression Levels inLeishmaniaInfantum-Infected Bone Marrow Dendritic Cells Evoke Regulatory Responses by Down-Regulating Interleukin-12 Production: Role of ERK1/2

“…Silent infection is a main feature of Leishmania strains causing nonhealing forms of the disease, since defects in DCs maturation may, in part, contribute to the unpolarized T cell phenotype occurring during these Leishmania infections. It is quite possible that a decline of IL-12/IL-IO ratio creates a microenviroment that aberrantly favours parasite establishment, since IL-IO enhances VL establishment by suppressing Th 1 cell activation and proliferation through the generation of Treg (24). Similarly, we showed that L. irifantum-infected BM-DCs produced significant levels of TNF-u and IL-I O.…”

“…These cells were characterized as high-level CD40 expressing DCs after L. major uptake (15). However, in our study only infected cells were characterized by (24,26). Silent infection is a main feature of Leishmania strains causing nonhealing forms of the disease, since defects in DCs maturation may, in part, contribute to the unpolarized T cell phenotype occurring during these Leishmania infections.…”

Leishmania infantum Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis

“…Pkm2 transcription has been related with macrophage [20,21] and NF-kB activation [22]. This phenomenon suggests that bystander macrophages could be activated in a similar fashion as it was demonstrated to occur with bystander dendritic cells [23,24] or even by infected macrophage secreted extracellular vesicles [25]. From the early energetic and metabolic settings responsible for a glycolytic environment resulted a nutrient and energetic deficit.…”