title: CD4+ natural regulatory T cells prevent experimental cerebral malaria via CTLA-4 when expanded in vivo.
abstract: Studies in malaria patients indicate that higher frequencies of peripheral blood CD4(+) Foxp3(+) CD25(+) regulatory T (Treg) cells correlate with increased blood parasitemia. This observation implies that Treg cells impair pathogen clearance and thus may be detrimental to the host during infection. In C57BL/6 mice infected with Plasmodium berghei ANKA, depletion of Foxp3(+) cells did not improve parasite control or disease outcome. In contrast, elevating frequencies of natural Treg cells in vivo using IL-2/anti-IL-2 complexes resulted in complete protection against severe disease. This protection was entirely dependent upon Foxp3(+) cells and resulted in lower parasite biomass, impaired antigen-specific CD4(+) T and CD8(+) T cell responses that would normally promote parasite tissue sequestration in this model, and reduced recruitment of conventional T cells to the brain. Furthermore, Foxp3(+) cell-mediated protection was dependent upon CTLA-4 but not IL-10. These data show that T cell-mediated parasite tissue sequestration can be reduced by regulatory T cells in a mouse model of malaria, thereby limiting malaria-induced immune pathology.
authors.affiliation: Immunology and Infection Laboratory, Queensland Institute of Medical Research and The Australian Centre for Vaccine Development, Herston, Brisbane, Queensland, Australia. ashraful.haque@qimr.edu.au
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.forename: Seri
authors.initials: S
authors.lastname: Mustafah
authors.forename: Laure
authors.initials: L
authors.lastname: Desbarrieres
authors.forename: Fabian
authors.initials: F
authors.lastname: de Labastida
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology; D060908:CTLA-4 Antigen; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors; D016753:Interleukin-10; D016779:Malaria, Cerebral / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000469:parasitology*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016753:Interleukin-10