Lymph-Node Resident CD8α ⁺ Dendritic Cells Capture Antigens from Migratory Malaria Sporozoites and Induce CD8 ⁺ T Cell Responses

Abstract

Malaria infection begins when a female Anopheles mosquito injects Plasmodium sporozoites into the skin of its host during blood feeding. Skin-deposited sporozoites may enter the bloodstream and infect the liver, reside and develop in the skin, or migrate to the draining lymph nodes (DLNs). Importantly, the DLN is where protective CD8 ⁺ T cell responses against malaria liver stages are induced after a dermal route of infection. However, the significance of parasites in the skin and DLN to CD8 ⁺ T cell activation is largely unknown. In this study, we used genetically modified parasites, as well as antibody-mediated immobilization of sporozoites, to determine that active sporozoite migration to the DLNs is required for robust CD8 ⁺ T cell responses. Through dynamic in vivo and static imaging, we show the direct uptake of parasites by lymph-node resident DCs followed by CD8 ⁺ T cell-DC cluster formation, a surrogate for antigen presentation, in the DLNs. A few hours after sporozoite arrival to the DLNs, CD8 ⁺ T cells are primed by resident CD8α ⁺ DCs with no apparent role for skin-derived DCs. Together, these results establish a critical role for lymph node resident CD8α ⁺ DCs in CD8 ⁺ T cell priming to sporozoite antigens while emphasizing a requirement for motile sporozoites in the induction of CD8 ⁺ T cell-mediated immunity.

Author Summary

Malaria is responsible for the deaths of 0.5–2 million people each year. A safe and effective vaccine is likely needed for the control or eradication of malaria. Immunization with irradiated sporozoites, the infectious stage of the parasite transmitted by mosquitoes, protects people against malaria through the activation of specialized effector cells called CD8 ⁺ T cells, which can eliminate live parasites. The induction of such malaria-specific CD8 ⁺ T cells is critically dependent on dendritic cells, a diverse population of antigen-presenting cells. It was previously unclear how dendritic cells acquire sporozoite antigens to induce the protective CD8 ⁺ T cell response. Using a combination of functional studies and high-resolution imaging, we report here that live sporozoites access skin-draining lymph nodes after infection and directly provide antigens to resident dendritic cells that in turn activate CD8 ⁺ T cells. These results underscore the importance of live, motile sporozoites in the induction of protective CD8 ⁺ T cell responses and provide a mechanistic understanding for the superior immunogenicity of whole parasite vaccines.