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.
| Original language | English |
|---|---|
| Article number | 263 |
| Journal | Frontiers in Immunology |
| Volume | 9 |
| DOIs | |
| Publication status | Published - 26 Feb 2018 |
Bibliographical note
AcknowledgmentsThis work was supported by the Priority Program of the German Research Foundation (DFG) (RI 1849/2-1 and 4-1) and the Wellcome Trust (102705). We gratefully acknowledge our Ethiopian partners at the Armauer Hansen Research Institute, Addis Ababa. Rawleigh Howe for excellent supervision of flow cytometry analysis performed at the Armauer Hansen Research Institute and Selfu Girma, Birtukan Endale, Genet Amare and Hareg Yetesh for technical support during the field trips and laboratory work.
Supplementary Material
The Supplementary Material for this article can be found online at http://www.frontiersin.org/articles/10.3389/fimmu.2018.00263/full#supplementary-material.
Keywords
- Curdlan
- β‐Glucan
- dectin‐1
- cutaneous leishmaniasis
- adaptive immunity
- dendritic cells
- Th1 and Th2 cells
Access to Document
- Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development
Copyright: © 2018 Zimara, Chanyalew, Aseffa, van Zandbergen, Lepenies, Schmid, Weiss, Rascle, Wege, Jantsch, Schatz, Brown and Ritter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. https://creativecommons.org/licenses/by/4.0/