title: Suppression of CD4+ Effector Responses by Naturally Occurring CD4+ CD25+ Foxp3+ Regulatory T Cells Contributes to Experimental Cerebral Malaria.
abstract: The role of naturally occurring CD4(+) CD25(+) Foxp3(+) regulatory T cells (nTreg) in the pathogenesis of cerebral malaria (CM), which involves both pathogenic T cell responses and parasite sequestration in the brain, is still unclear. To assess the contribution and dynamics of nTreg during the neuropathogenesis, we unbalanced the ratio between nTreg and naive CD4(+) T cells in an attenuated model of Plasmodium berghei ANKA-induced experimental CM (ECM) by using a selective cell enrichment strategy. We found that nTreg adoptive transfer accelerated the onset and increased the severity of CM in syngeneic C57BL/6 (B6) P. berghei ANKA-infected mice without affecting the level of parasitemia. In contrast, naive CD4(+) T cell enrichment prevented CM and promoted parasite clearance. Furthermore, early during the infection nTreg expanded in the spleen but did not efficiently migrate to the site of neuroinflammation, suggesting that nTreg exert their pathogenic action early in the spleen by suppressing the protective naive CD4(+) T cell response to P. berghei ANKA infection in vivo in both CM-susceptible (B6) and CM-resistant (B6-CD4(-/-)) mice. However, their sole transfer was not sufficient to restore CM susceptibility in two CM-resistant congenic strains tested. Altogether, these results demonstrate that nTreg are activated and functional during P. berghei ANKA infection and that they contribute to the pathogenesis of CM. They further suggest that nTreg may represent an early target for the modulation of the immune response to malaria.
authors.affiliation: Département d'Immunologie, Institut Pasteur, Paris, France Université Pierre et Marie Curie, Paris, France Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Anne-Laurence
authors.initials: AL
authors.lastname: Blanc
authors.affiliation: Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Tarun
authors.initials: T
authors.lastname: Keswani
authors.affiliation: Unité d'Immunologie Moléculaire des Parasites, Institut Pasteur, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gorgette
authors.affiliation: Département d'Immunologie, Institut Pasteur, Paris, France Unité de Biologie des Populations Lymphocytaires, Institut Pasteur, Paris, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bandeira
authors.affiliation: INSERM U 631-CNRS UMR 6102, Université de la Méditerranée, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.affiliation: Département d'Immunologie, Institut Pasteur, Paris, France Université Pierre et Marie Curie, Paris, France CNRS UMR 7211, Université Pierre et Marie Curie, Hôpital de la Pitié-Salpêtrière, Paris, France Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Cazenave
authors.affiliation: Département d'Immunologie, Institut Pasteur, Paris, France Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France sylviane.pied@pasteur-lille.fr.
authors.forename: Sylviane
authors.identifier: http://orcid.org/0000-0003-0642-1423
authors.initials: S
authors.lastname: Pied
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology* / Q000469:parasitology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010962:Plasmodium berghei / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit