Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development
Creators: name: Zimara, Nicole
name: Chanyalew, Menberework
name: Aseffa, Abraham
name: van Zandbergen, Ger
name: Lepenies, Bernd
name: Schmid, Maximilian
name: Weiss, Richard
name: Rascle, Anne
name: Wege, Anja Kathrin
name: Jantsch, Jonathan
name: Schatz, Valentin
name: Brown, Gordon D.
name: Ritter, Uwe
Publisher: name: Universität Regensburg
Year: 2018
Subjects: subject: BETA-GLUCAN RECEPTOR; MURINE CUTANEOUS LEISHMANIASIS; C-TYPE LECTIN-1; CD4(+) T-CELLS; REAL-TIME PCR; BALB/C MICE; LANGERHANS CELLS; CANDIDA-ALBICANS; VISCERAL LEISHMANIASIS; INTERFERON-GAMMA; Curdlan; beta-glucan; Dectin-1; cutaneous leishmaniasis; adaptive immunity; dendritic cells; T helper 1 and T helper 2 cells
subject: 610 Medizin

description: 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-gamma 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.