Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis.
Experimental cerebral malaria (ECM) resulting from Plasmodium berghei ANKA infection involves T lymphocytes. However, the mechanisms of T cell-mediated pathogenesis remain unknown. We found that, in contrast to ECM-susceptible C57BL6 mice, perforin-deficient (PFP-KO) mice were resistant to ECM in the absence of brain lesions, whereas cytoadherence of parasitized erythrocytes and massive accumulation of activated/effector CD8 lymphocytes were observed in both groups of mice. ECM is induced in PFP-KO mice after adoptive transfer of cytotoxic CD8+ cells from infected C57BL6 mice, which were directed to the brain of PFP-KO mice. This specific recruitment might involve chemokine/chemokine receptors, since their expression was up-regulated on activated CD8 cells, and susceptibility to ECM was delayed in CCR5-KO mice. Thus, lymphocyte cytotoxicity and cell trafficking are key players in ECM pathogenesis.
Nitcheu
Josianne
J
Institut National de la Santé et de la Recherche Médicale, Unité 511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, CHU Pitie-Salpétrière, Université Pierre et Marie Curie, 91 boulevard de l'Hôpital, 75634 Paris Cedex 13, France.
Bonduelle
Olivia
O
Combadiere
Christophe
C
Tefit
Maurel
M
Seilhean
Danielle
D
Mazier
Dominique
D
Combadiere
Behazine
B
D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D016779:Malaria, Cerebral / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin; D010962:Plasmodium berghei / Q000276:immunology* / Q000472:pathogenicity; D052899:Pore Forming Cytotoxic Proteins; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D013154:Spleen / Q000737:chemistry / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D013388:Succinimides / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019713:Receptors, CCR5; D013388:Succinimides; D054353:Perforin