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

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.

Responses of Intestinal Microbiota and Immunity to Increasing Dietary Levels of Iron Using a Piglet Model

“…CLEC7A, a member of C-type lectin receptors, is produced by myeloid cells to sense pathogens and bacterial infections and could activate immune cells in diarrhea-predominant irritable bowel syndrome (Chi et al, 2020). CLE7A and toll-like receptors (TLRs) could be independent or together to activate immunocytes, such as dendritic cells and T-helper-type 1 (Th1) cells, further inducing IFN-γ production (Loures et al, 2015;Perkins and Vogel, 2015;Zimara et al, 2018). IFN-induced proteins with tetratricopeptide repeats (IFITs) could be generated through the IFN-γ-JAK-STAT1/2 pathway to fight against pathogen infection, and IFIT1-deficiency mice are more sensitive to Burkholderia cenocepacia (Van Treuren and Dodd, 2020;Zheng et al, 2020).…”

C-Type Lectins in Veterinary Species: Recent Advancements and Applications

“…A strong correlation between the protective Th1 response and Dectin-1 engagement was recently shown in mouse Leishmania spp. infections models [ 76 , 77 ], demonstrating a crucial role of this specific CTL in anti- Leishmania immunity. The site-specific expansion of Dectin-1 expressing DCs following intradermal injection of the specific Dectin-1 agonist curdlan sufficed to protect wild-type mice from illness following transdermal Leishmania infection, whereas Dectin-1 −/− mice succumbed to the disease [ 76 ].…”

“…infections models [ 76 , 77 ], demonstrating a crucial role of this specific CTL in anti- Leishmania immunity. The site-specific expansion of Dectin-1 expressing DCs following intradermal injection of the specific Dectin-1 agonist curdlan sufficed to protect wild-type mice from illness following transdermal Leishmania infection, whereas Dectin-1 −/− mice succumbed to the disease [ 76 ]. Leishmaniosis is an important and life-threatening disease in dogs; an insufficient Th1 response in favor of the detrimental Th2 response [ 78 ] in clinically affected canids renders vaccine development a significant challenge [ 79 , 80 ].…”

“…As a potential treatment of parasitic infections, T-cell modulation toward the favorable T helper type 1 response was achieved via the metaphylactic curdlan stimulation of Dectin-1 expressing DCs in the mouse model of cutaneous leishmaniosis. In this model, the co-injection of curdlan along with infectious L. major promastigotes resulted in a resistant phenotype observed in the otherwise highly susceptible BALB/c mouse strain [ 76 ]. This finding matches the protective properties of yeast glucans that had previously been described in murine leishmaniosis models [ 118 , 119 ].…”

Molecular Aspects of Dendritic Cell Activation in Leishmaniasis: An Immunobiological View

“…These researchers observed an increased expansion of Dectin-1 + DCs following L. major inoculation in C57BL/6 and BALB/c mice as well as in the peripheral blood of CL patients. Additionally, experiments with BMDM stimulated with a Dectin-1 agonist revealed both high levels of DC maturation and the expansion of CD 4 T cells (56). Collectively, these findings serve to indicate the significance of both CTRL signaling and the physical interactions between these cells and pathogens in the promotion of an effective immune response.…”