title: Damage to the blood-brain barrier during experimental cerebral malaria results from synergistic effects of CD8+ T cells with different specificities.
abstract: CD8(+) T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8(+) epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8(+) T cells. Induction and functionality of these specific CD8(+) T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8(+) T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-γ], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrier in vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8(+) T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8(+) T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8(+) T cell responses that are involved in ECM.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chek Meng
authors.initials: CM
authors.lastname: Poh
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Shanshan W
authors.initials: SW
authors.lastname: Howland
authors.affiliation: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore.
authors.forename: Gijsbert M
authors.initials: GM
authors.lastname: Grotenbreg
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore renia_laurent@immunol.a-star.edu.sg.
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001812:Blood-Brain Barrier; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D000939:Epitopes; D005786:Gene Expression Regulation / Q000276:immunology; D016779:Malaria, Cerebral / Q000150:complications* / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*
chemical_list: D000939:Epitopes