CCR7-dependent immunity during acute Toxoplasma gondii infection.
The chemokine receptor CCR7 is a well-established homing receptor for dendritic cells and T cells. Interactions with its ligands, CCL19 and CCL21, facilitate priming of immune responses in lymphoid tissue, yet CCR7-independent immune responses can be generated in the presence of sufficient antigen. In these studies, we investigated the role of CCR7 signaling in the generation of protective immune responses to the intracellular protozoan parasite Toxoplasma gondii. The results demonstrated a significant increase in the expression of CCL19, CCL21, and CCR7 in peripheral and central nervous system (CNS) tissues over the course of infection. Unexpectedly, despite the presence of abundant antigen, CCR7 was an absolute requirement for protective immunity to T. gondii, as CCR7(-/-) mice succumbed to the parasite early in the acute phase of infection. Although serum levels of interleukin 12 (IL-12), IL-6, tumor necrosis factor alpha (TNF-alpha), and IL-10 remained unchanged, there was a significant decrease in CCL2/monocyte chemoattractant protein 1 (MCP-1) and inflammatory monocyte recruitment to the site of infection. In addition, CCR7(-/-) mice failed to produce sufficient gamma interferon (IFN-gamma), a critical Th1-associated effector cytokine required to control parasite replication. As a result, there was increased parasite dissemination and a significant increase in parasite burden in the lungs, livers, and brains of infected mice. Adoptive-transfer experiments revealed that expression of CCR7 on the T-cell compartment alone is sufficient to enable T-cell priming, increase IFN-gamma production, and allow the survival of CCR7(-/-) mice. These data demonstrate an absolute requirement for T-cell expression of CCR7 for the generation of protective immune responses to Toxoplasma infection.
Noor
Shahani
S
Division of Biomedical Sciences, University of California, 1626 Statistics Building, 3401 Watkins Drive, Riverside, CA 92521, USA.
Habashy
Andrew S
AS
Nance
J Philip
JP
Clark
Robin T
RT
Nemati
Kiav
K
Carson
Monica J
MJ
Wilson
Emma H
EH
D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000469:parasitology; D054415:Chemokine CCL19 / Q000096:biosynthesis; D018932:Chemokine CCL2 / Q000378:metabolism; D054421:Chemokine CCL21 / Q000096:biosynthesis; D020869:Gene Expression Profiling; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000469:parasitology; D008168:Lung / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*
C515461:Ccl19 protein, mouse; C491768:Ccl2 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D018932:Chemokine CCL2; D054421:Chemokine CCL21; D054400:Receptors, CCR7; D007371:Interferon-gamma