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      Type I Interferons Induce T Regulatory 1 Responses and Restrict Humoral Immunity during Experimental Malaria

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          Abstract

          CD4 T cell-dependent antibody responses are essential for limiting Plasmodium parasite replication and the severity of malaria; however, the factors that regulate humoral immunity during highly inflammatory, Th1-biased systemic infections are poorly understood. Using genetic and biochemical approaches, we show that Plasmodium infection-induced type I interferons limit T follicular helper accumulation and constrain anti-malarial humoral immunity. Mechanistically we show that CD4 T cell-intrinsic type I interferon signaling induces T-bet and Blimp-1 expression, thereby promoting T regulatory 1 responses. We further show that the secreted effector cytokines of T regulatory 1 cells, IL-10 and IFN-γ, collaborate to restrict T follicular helper accumulation, limit parasite-specific antibody responses, and diminish parasite control. This circuit of interferon-mediated Blimp-1 induction is also operational during chronic virus infection and can occur independently of IL-2 signaling. Thus, type I interferon-mediated induction of Blimp-1 and subsequent expansion of T regulatory 1 cells represent generalizable features of systemic, inflammatory Th1-biased viral and parasitic infections that are associated with suppression of humoral immunity.

          Author Summary

          Humoral immunity is essential for host resistance to pathogens that trigger highly inflammatory immune responses, including Plasmodium parasites, the causative agents of malaria. Long-lived, secreted antibody responses depend on a specialized subset of CD4 T cells called T follicular helper (Tfh) cells. However, anti- Plasmodium humoral immunity is often short-lived, non-sterilizing, and immunity rapidly wanes, leaving individuals susceptible to repeated bouts of malaria. Here we explored the relationship between inflammatory type I interferons, the regulation of pathogen-specific CD4 T cell responses, and humoral immunity using models of experimental malaria and systemic virus infection. We identified that type I interferons promote the formation and accumulation of pathogen-specific CD4 T regulatory 1 cells that co-express interferon-gamma and interleukin-10. Moreover, we show that the combined activity of interferon-gamma and interleukin-10 limits the magnitude of infection-induced Tfh responses, the secretion of parasite-specific secreted antibody, and parasite control. Our study provides new insight into the regulation of T regulatory 1 responses and humoral immunity during inflammatory immune reactions against systemic infections.

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          Most cited references 72

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          Follicular helper CD4 T cells (TFH).

           Shane Crotty (2010)
          T cell help to B cells is a fundamental aspect of adaptive immunity and the generation of immunological memory. Follicular helper CD4 T (T(FH)) cells are the specialized providers of B cell help. T(FH) cells depend on expression of the master regulator transcription factor Bcl6. Distinguishing features of T(FH) cells are the expression of CXCR5, PD-1, SAP (SH2D1A), IL-21, and ICOS, among other molecules, and the absence of Blimp-1 (prdm1). T(FH) cells are important for the formation of germinal centers. Once germinal centers are formed, T(FH) cells are needed to maintain them and to regulate germinal center B cell differentiation into plasma cells and memory B cells. This review covers T(FH) differentiation, T(FH) functions, and human T(FH) cells, discussing recent progress and areas of uncertainty or disagreement in the literature, and it debates the developmental relationship between T(FH) cells and other CD4 T cell subsets (Th1, Th2, Th17, iTreg).
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            The regulation of IL-10 production by immune cells.

            Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.
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              IFNalpha activates dormant haematopoietic stem cells in vivo.

              Maintenance of the blood system is dependent on dormant haematopoietic stem cells (HSCs) with long-term self-renewal capacity. After injury these cells are induced to proliferate to quickly re-establish homeostasis. The signalling molecules promoting the exit of HSCs out of the dormant stage remain largely unknown. Here we show that in response to treatment of mice with interferon-alpha (IFNalpha), HSCs efficiently exit G(0) and enter an active cell cycle. HSCs respond to IFNalpha treatment by the increased phosphorylation of STAT1 and PKB/Akt (also known as AKT1), the expression of IFNalpha target genes, and the upregulation of stem cell antigen-1 (Sca-1, also known as LY6A). HSCs lacking the IFNalpha/beta receptor (IFNAR), STAT1 (ref. 3) or Sca-1 (ref. 4) are insensitive to IFNalpha stimulation, demonstrating that STAT1 and Sca-1 mediate IFNalpha-induced HSC proliferation. Although dormant HSCs are resistant to the anti-proliferative chemotherapeutic agent 5-fluoro-uracil, HSCs pre-treated (primed) with IFNalpha and thus induced to proliferate are efficiently eliminated by 5-fluoro-uracil exposure in vivo. Conversely, HSCs chronically activated by IFNalpha are functionally compromised and are rapidly out-competed by non-activatable Ifnar(-/-) cells in competitive repopulation assays. Whereas chronic activation of the IFNalpha pathway in HSCs impairs their function, acute IFNalpha treatment promotes the proliferation of dormant HSCs in vivo. These data may help to clarify the so far unexplained clinical effects of IFNalpha on leukaemic cells, and raise the possibility for new applications of type I interferons to target cancer stem cells.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                12 October 2016
                October 2016
                : 12
                : 10
                Affiliations
                [1 ]Departments of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
                [2 ]Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
                [3 ]Graduate Program in Biosciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America
                McGill University, CANADA
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: RAZ NSB.

                • Data curation: RAZ JJG ACG RLP BEB NSB.

                • Formal analysis: RAZ JJG ACG RLP BEB NSB.

                • Funding acquisition: NSB.

                • Investigation: RAZ JJG ACG RLP BEB NSB.

                • Project administration: NSB.

                • Resources: DJJC.

                • Supervision: NSB.

                • Visualization: RAZ JJG ACG RLP BEB NSB.

                • Writing – original draft: RAZ NSB.

                • Writing – review & editing: RAZ NSB.

                Article
                PPATHOGENS-D-16-00861
                10.1371/journal.ppat.1005945
                5061386
                27732671
                © 2016 Zander et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 6, Tables: 0, Pages: 23
                Product
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI125446
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI053108
                Award Recipient : Daniel J.J. Carr
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI007633
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: AI099070
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000968, American Heart Association;
                Award ID: 16PRE27660002
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: GM103447
                Award Recipient :
                This work was supported in part by grants from the National Institute of Allergy and Infectious Disease (T32AI007633 to RAZ; 1K22AI099070 and R01AI125446 to NSB; R01AI053108 to DJJC) and the American Heart Association (16PRE27660002 to JJG). NSB is also an OK-INBRE scholar supported by a grant from the National Institute of General Medical Sciences (8P20GM103447). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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