Murine malaria is exacerbated by CTLA-4 blockade.
Cytolytic T lymphocyte-associated Ag-4 (CD152) is a negatively regulating molecule, which is primarily expressed on T cells following their activation. In this study, we have examined the role of CTLA-4 expression in experimental blood-stage malaria. Similar to human malaria, CTLA-4 is expressed on CD4(+) T cells of C57BL/6 mice after infection with Plasmodium berghei. A kinetic analysis revealed that CTLA-4 expression was increased on day 5 postinfection and reached a peak on day 9 postinfection, when almost 10% of splenic CD4(+) T cells expressed CTLA-4. Blockade of CTLA-4 in vivo by a specific mAb and subsequent challenge with P. berghei caused neurological signs reminiscent of murine cerebral malaria and earlier death. Histologic examination of brain sections from anti-CTLA-4-treated mice revealed pathologic changes such as hemorrhages and edema, which were absent in control mice. Furthermore, treatment with anti-CTLA-4 also reversed the extensive loss of CD4(+) T cells and the suppressed T cell response occurring during blood-stage malaria. Our data suggest that CTLA-4 expression prevents immune pathology by restricting T cell activation during malaria. They also indicate that the development of cerebral malaria is mediated by a failure to down-regulate T cell activation.
Jacobs
Thomas
T
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. tjacobs@bni.uni-hamburg.de
Graefe
Sebastian E B
SE
Niknafs
Sonja
S
Gaworski
Iris
I
Fleischer
Bernhard
B
D000069594:Abatacept; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology* / Q000502:physiology; D001921:Brain / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018796:Immunoconjugates; D007274:Injections, Intraperitoneal; D008099:Liver / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008288:Malaria / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D016779:Malaria, Cerebral / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept