CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes.
The success of immunization with irradiated sporozoites is unparalleled among the current vaccination approaches against malaria, but its mechanistic underpinnings have yet to be fully elucidated. Using a model mimicking natural infection by Plasmodium yoelii, we delineated early events governing the development of protective CD8(+) T-cell responses to the circumsporozoite protein. We demonstrate that dendritic cells in cutaneous lymph nodes prime the first cohort of CD8(+) T cells after an infectious mosquito bite. Ablation of these lymphoid sites greatly impairs subsequent development of protective immunity. Activated CD8(+) T cells then travel to systemic sites, including the liver, in a sphingosine-1-phosphate (S1P)-dependent fashion. These effector cells, however, no longer require bone marrow-derived antigen-presenting cells for protection; instead, they recognize antigen on parenchymal cells-presumably parasitized hepatocytes. Therefore, we report an unexpected dichotomy in the tissue restriction of host responses during the development and execution of protective immunity to Plasmodium.
Chakravarty
Sumana
S
Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, Maryland 21205, USA.
Cockburn
Ian A
IA
Kuk
Salih
S
Overstreet
Michael G
MG
Sacci
John B
JB
Zavala
Fidel
F
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006801:Humans; D008099:Liver / Q000469:parasitology*; D008198:Lymph Nodes / Q000276:immunology*; D008212:Lymphocyte Depletion; D008288:Malaria / Q000276:immunology*; D051379:Mice; D010967:Plasmodium yoelii / Q000276:immunology; D012867:Skin / Q000276:immunology*; D013156:Splenectomy
D000953:Antigens, Protozoan