Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response

Abstract

Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4 ⁺ T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved.

Author Summary

Prior studies in mice have shown that the inoculation of Leishmania major into the skin by sand fly bite or by needle provokes a massive recruitment of neutrophils that take up the parasite, and that this response somehow suppresses immunity since neutrophil depletion results in better control of the infection. We investigated how neutrophils recruited to the injection site might interact with and suppress the function of dendritic cells (DCs) in the skin. Infected neutrophils recovered from the skin expressed increased levels of apoptotic markers compared to uninfected neutrophils, and were efficiently taken up by dermal DCs when injected back into the skin. When dermal DCs were permitted to take up parasites in the absence of neutrophils, their expression of activation markers and their ability to present Leishmania antigens were enhanced. Neutrophil depletion also enhanced the activation of Leishmania specific CD4 ⁺ T cells in vivo. The results suggest that for insect borne pathogens like Leishmania that provoke a strong inflammatory response at the site of infection, the immunosuppressive effects associated with the apoptotic cell clearance function of DCs will inhibit the early development of immunity.