title: Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation.
abstract: Naturally acquired immunity to malaria develops only after years of repeated exposure to Plasmodium parasites. Despite the key role antibodies play in protection, the cellular processes underlying the slow acquisition of immunity remain unknown. Using mouse models, we show that severe malaria infection inhibits the establishment of germinal centers (GCs) in the spleen. We demonstrate that infection induces high frequencies of T follicular helper (Tfh) cell precursors but results in impaired Tfh cell differentiation. Despite high expression of Bcl-6 and IL-21, precursor Tfh cells induced during infection displayed low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3. Blockade of the inflammatory cytokines TNF and IFN-γ or T-bet deletion restored Tfh cell differentiation and GC responses to infection. Thus, this study demonstrates that the same pro-inflammatory mediators that drive severe malaria pathology have detrimental effects on the induction of protective B cell responses.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ryg-Cornejo
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Lisa Julia
authors.initials: LJ
authors.lastname: Ioannidis
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Ann
authors.initials: A
authors.lastname: Ly
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Chris Yu
authors.initials: CY
authors.lastname: Chiu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: Tellier
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Danika Lea
authors.initials: DL
authors.lastname: Hill
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Simon Peter
authors.initials: SP
authors.lastname: Preston
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Marc
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Molecular Immunomodulation Laboratory, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, VIC 3800, Australia; Centre for Inflammatory Diseases, School of Clinical Sciences, Monash University, Melbourne, VIC 3800, Australia.
authors.forename: Di
authors.initials: D
authors.lastname: Yu
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Stephen Laurence
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: kallies@wehi.edu.au.
authors.forename: Axel
authors.initials: A
authors.lastname: Kallies
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: hansen@wehi.edu.au.
authors.forename: Diana Silvia
authors.initials: DS
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D008288:Malaria / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010961:Plasmodium / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: C490010:Bcl6 protein, mouse; C513179:CXCR5 protein, mouse; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051560:Proto-Oncogene Proteins c-bcl-6; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor