Blocking Junctional Adhesion Molecule C Enhances Dendritic Cell Migration and Boosts the Immune Responses against Leishmania major

Abstract

The recruitment of dendritic cells to sites of infections and their migration to lymph nodes is fundamental for antigen processing and presentation to T cells. In the present study, we showed that antibody blockade of junctional adhesion molecule C (JAM-C) on endothelial cells removed JAM-C away from junctions and increased vascular permeability after L. major infection. This has multiple consequences on the output of the immune response. In resistant C57BL/6 and susceptible BALB/c mice, we found higher numbers of innate immune cells migrating from blood to the site of infection. The subsequent migration of dendritic cells (DCs) from the skin to the draining lymph node was also improved, thereby boosting the induction of the adaptive immune response. In C57BL/6 mice, JAM-C blockade after L. major injection led to an enhanced IFN-γ dominated T helper 1 (Th1) response with reduced skin lesions and parasite burden. Conversely, anti JAM-C treatment increased the IL-4-driven T helper 2 (Th2) response in BALB/c mice with disease exacerbation. Overall, our results show that JAM-C blockade can finely-tune the innate cell migration and accelerate the consequent immune response to L. major without changing the type of the T helper cell response.

Author Summary

Leishmaniasis is a parasitic disease transmitted to humans through sand fly bites. Clinical symptoms vary from self-healing cutaneous lesions to death. Cutaneous leishmaniasis is particularly studied in mice inoculated with Leishmania major. In this model, some strains (e.g. C57BL/6) are resistant due to a Th1 immune response promoting parasite killing. Conversely, other strains (e.g. BALB/c) are susceptible due to a nonprotective Th2 response. DCs are professional antigen-presenting cells that educate antigen-specific T cells. Improving the migration of DCs from the site of infection to the lymph nodes, where T cells reside, may improve the T cell response. JAM-C is a vascular adhesion molecule implicated in leukocyte migration in different inflammatory models. We found that JAM-C blockade with antibodies increases vascular permeability and consequently improves the migration of DCs to sites of infection and draining lymph nodes. This increased leukocyte migration boosted the induction of the Th1 response in resistant mice, while in susceptible mice the Th2 response was augmented. This led to disease improvement or exacerbation, respectively. Our results illustrate the key role of a vascular adhesion molecule in controlling leukocyte migration and the subsequent immune events in response to pathogen infections.