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      T follicular helper cells regulate the activation of B lymphocytes and antibody production during Plasmodium vivax infection

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          Abstract

          Although the importance of humoral immunity to malaria has been established, factors that control antibody production are poorly understood. Follicular helper T cells (Tfh cells) are pivotal for generating high-affinity, long-lived antibody responses. While it has been proposed that expansion of antigen-specific Tfh cells, interleukin (IL) 21 production and robust germinal center formation are associated with protection against malaria in mice, whether Tfh cells are found during Plasmodium vivax ( P. vivax) infection and if they play a role during disease remains unknown. Our goal was to define the role of Tfh cells during P. vivax malaria. We demonstrate that P. vivax infection triggers IL-21 production and an increase in Tfh cells (PD-1+ICOS+CXCR5+CD45RO+CD4+CD3+). As expected, FACS-sorted Tfh cells, the primary source of IL-21, induced immunoglobulin production by purified naïve B cells. Furthermore, we found that P. vivax infection alters the B cell compartment and these alterations were dependent on the number of previous infections. First exposure leads to increased proportions of activated and atypical memory B cells and decreased frequencies of classical memory B cells, whereas patients that experienced multiple episodes displayed lower proportions of atypical B cells and higher frequencies of classical memory B cells. Despite the limited sample size, but consistent with the latter finding, the data suggest that patients who had more than five infections harbored more Tfh cells and produce more specific antibodies. P. vivax infection triggers IL-21 production by Tfh that impact B cell responses in humans.

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          Plasmodium vivax is the most widely spread malaria parasite species and represents a significant impediment to social and economic development in endemic countries. Our goal was to assess the importance of T follicular helper cells in the development of the immune response during malaria. We found that P. vivax infection promotes expansion of circulating Tfh cells that secrete IL-21 to boost immunoglobulin production by B-cells. Accordingly, malaria infection led to marked changes in B cell subpopulations, including expansion of plasma cells and increased production of antigen-specific IgG1 and IgG3. Re-exposure to P. vivax led to amplified Tfh cells cell responses that were concomitantly associated with increased frequencies of classical memory B cells. Thus, Tfh cells that are induced during P. vivax infection could impact the efficiency of humoral immune responses that underlie protective immunity.

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          Most cited references37

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          Follicular B Helper T Cells Express Cxc Chemokine Receptor 5, Localize to B Cell Follicles, and Support Immunoglobulin Production

          Chemokines and their receptors have been identified as major regulators controlling the functional organization of secondary lymphoid organs. Here we show that expression of CXC chemokine receptor 5 (CXCR5), a chemokine receptor required for B cell homing to B cell follicles, defines a novel subpopulation of B helper T cells localizing to follicles. In peripheral blood these cells coexpress CD45RO and the T cell homing CC chemokine receptor 7 (CCR7). In secondary lymphoid organs, CD4+CXCR5+ cells lose expression of CCR7, which allows them to localize to B cell follicles and germinal centers where they express high levels of CD40 ligand (CD40L), a costimulatory molecule required for B cell activation and inducible costimulator (ICOS), a recently identified costimulatory molecule of the CD28 family. Thus, when compared with CD4+CD45RO+CXCR5− cells, CD4+CD45RO+CXCR5+ tonsillar T cells efficiently support the production of immunoglobulin (Ig)A and IgG. In contrast, analysis of the memory response revealed that long-lasting memory cells are found within the CD4+CD45RO+CXCR5− population, suggesting that CXCR5+CD4 cells represent recently activated effector cells. Based on the characteristic localization within secondary lymphoid organs, we suggest to term these cells “follicular B helper T cells” (TFH).
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            Proinflammatory T helper type 17 cells are effective B-cell helpers.

            T helper type 17 (TH17) cells are highly proinflammatory effector T cells that are characterized by the production of high amounts of IL-17A, IL-17F, IL-21, and IL-22. Furthermore, TH17 cells have been associated with a number of autoimmune diseases. However, it is not clear whether TH17 cells can also serve as effective helper cells. Here we show that TH17 cells can function as B-cell helpers in that they not only induce a strong proliferative response of B cells in vitro but also trigger antibody production with class switch recombination in vivo. Transfer of TH17 cells into WT or T-cell receptor alpha-deficient mice, which lack endogenous T cells, induces a pronounced antibody response with preferential isotype class switching to IgG1, IgG2a, IgG2b, and IgG3, as well as the formation of germinal centers. Conversely, blockade of IL-17 signaling results in a significant reduction in both number and size of germinal centers. Whereas IL-21 is known to help B cells, IL-17 on its own drives B cells to undergo preferential isotype class switching to IgG2a and IgG3 subtypes. These observations provide insights into the unappreciated role of TH17 cells and their signature cytokines in mediating B-cell differentiation and class switch recombination.
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              Follicular helper T cells: lineage and location.

              Follicular helper T (Tfh) cells are the class of effector T helper cells that regulates the step-wise development of antigen-specific B cell immunity in vivo. Deployment of CXCR5+ Tfh cells to B cell zones of lymphoid tissues and stable cognate interactions with B cells are central to the delivery of antigen-specific Tfh cell function. Here, we review recent advances that have helped to unravel distinctive elements of developmental programming for Tfh cells and unique effector Tfh cell functions focused on antigen-primed B cells. Understanding the regulatory functions of Tfh cells in the germinal center and the subsequent regulation of memory B cell responses to antigen recall represent the frontiers of this research area with the potential to alter fundamentally the design of future vaccines.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: Resources
                Role: Resources
                Role: MethodologyRole: ResourcesRole: Writing – review & editing
                Role: Formal analysisRole: ResourcesRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                10 July 2017
                July 2017
                : 13
                : 7
                : e1006484
                Affiliations
                [1 ] Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
                [2 ] Laboratório de Imunopatologia, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
                [3 ] Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
                [4 ] Laboratório de Malária, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
                [5 ] Centro de Pesquisas em Medicina Tropical de Rondônia, Porto Velho, Rondônia, Brazil
                [6 ] Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, São Paulo, Brazil
                [7 ] Laboratório de Biomarcadores de Diagnóstico e Monitoração, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
                [8 ] Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
                Queensland Institute of Medical Research, AUSTRALIA
                Author notes

                The authors have declared that no competing interest exist.

                Author information
                http://orcid.org/0000-0003-2538-5878
                http://orcid.org/0000-0003-2470-8559
                http://orcid.org/0000-0002-7761-5498
                http://orcid.org/0000-0002-4969-8812
                Article
                PPATHOGENS-D-17-00317
                10.1371/journal.ppat.1006484
                5519210
                28700710
                b87d2428-b257-476d-8d35-7fbeb09f7e94

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 15 February 2017
                : 21 June 2017
                Page count
                Figures: 7, Tables: 0, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: DECIT (483098/2011-6)
                Award Recipient :
                Funded by: FAPEMIG
                Award ID: INCTV (MS-CBB-APQ00077-09)
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: INCTV 573547/2008-4
                Award Recipient :
                Funded by: Fiocruz
                Award ID: PAPES VI
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100002322, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior;
                Award ID: CAPES
                Award Recipient :
                This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq (DECIT) (483098/2011-6), FAPEMIG, National Institute of Science and Technology for Vaccines (CNPq-573547/2008- 4/FAPEMIG/MS-CBB-APQ 00077-09), FIOCRUZ (PAPES VI), PRONEX-Malaria CBB APQ-01355-14 and NIAID/ICEMR/U19 AI089681 and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior. LRVA, ISS, OAMF and RTG are CNPq fellows (PQ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                All relevant data are within the paper and its Supporting Information files.

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