Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development.

Nicole Zimara,Abraham Aseffa,Jonathan Jantsch,Valentin Schatz,Maximilian Schmid,Richard Weiss,Ger Van Zandbergen,Anne Rascle,Anja Kathrin Wege,Bernd Lepenies,Uwe Ritter,Menberework Chanyalew,Gordon D Brown

doi:10.3389/fimmu.2018.00263

Abstract

Resistant mouse strains mount a protective T cell-mediated immune response upon infection with Leishmania (L.) parasites. Healing correlates with a T helper (Th) cell-type 1 response characterized by a pronounced IFN-γ production, while susceptibility is associated with an IL-4-dependent Th2-type response. It has been shown that dermal dendritic cells are crucial for inducing protective Th1-mediated immunity. Additionally, there is growing evidence that C-type lectin receptor (CLR)-mediated signaling is involved in directing adaptive immunity against pathogens. However, little is known about the function of the CLR Dectin-1 in modulating Th1- or Th2-type immune responses by DC subsets in leishmaniasis. We characterized the expression of Dectin-1 on CD11c+ DCs in peripheral blood, at the site of infection, and skin-draining lymph nodes of L. major-infected C57BL/6 and BALB/c mice and in peripheral blood of patients suffering from cutaneous leishmaniasis (CL). Both mouse strains responded with an expansion of Dectin-1+ DCs within the analyzed tissues. In accordance with the experimental model, Dectin-1+ DCs expanded as well in the peripheral blood of CL patients. To study the role of Dectin-1+ DCs in adaptive immunity against L. major, we analyzed the T cell stimulating potential of bone marrow-derived dendritic cells (BMDCs) in the presence of the Dectin-1 agonist Curdlan. These experiments revealed that Curdlan induces the maturation of BMDCs and the expansion of Leishmania-specific CD4+ T cells. Based on these findings, we evaluated the impact of Curdlan/Dectin-1 interactions in experimental leishmaniasis and were able to demonstrate that the presence of Curdlan at the site of infection modulates the course of disease in BALB/c mice: wild-type BALB/c mice treated intradermally with Curdlan developed a protective immune response against L. major whereas Dectin-1−/− BALB/c mice still developed the fatal course of disease after Curdlan treatment. Furthermore, the vaccination of BALB/c mice with a combination of soluble L. major antigens and Curdlan was able to provide a partial protection from severe leishmaniasis. These findings indicate that the ligation of Dectin-1 on DCs acts as an important checkpoint in adaptive immunity against L. major and should therefore be considered in future whole-organism vaccination strategies.

Highlights

Cutaneous leishmaniasis (CL) is a vector-borne parasitic infectious disease encountered in tropical and subtropical regions of the world [1]
Based on the potential role of Dectin-1+ DCs in adaptive immunity, we addressed the question whether a cutaneous infection with Leishmania parasites results in an expansion of Dectin-1+ DCs
Other groups demonstrated that an i.v. immunization with β-glucans combined with killed parasites induced a reduction in the parasite load in visceral organs of BALB/c and C57BL/6 mice [46, 109] and that CF-1 mice developed a milder course of visceral leishmaniasis (VL), if they had been pretreated s.c. or i.v. with β-glucans in combination with killed L. donovani parasites [43, 110]

Summary

Introduction

Cutaneous leishmaniasis (CL) is a vector-borne parasitic infectious disease encountered in tropical and subtropical regions of the world [1]. Different clinical manifestations in humans, ranging from a self-limiting cutaneous infection to disseminating visceral leishmaniasis (VL), are described with respect to the transmitting vectors and Leishmania species [2]. Comparable to the course of disease in humans, L. major parasites can develop cutaneous manifestations in C57BL/6 and BALB/c mouse models [3]. It is known that L. major parasites require phagocytic cells for replication and spreading within the host [4]. In this regard, neutrophils and macrophages play a pivotal role as host cells for the initial survival and spreading of parasites. CD4+ T cells are crucial key players in modulating antigen-specific immunity in leishmaniasis [3]

Methods

Results

Conclusion