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During Malaria Infection Protection from Severe Immunopathology T IL-27 Promotes IL-10 Production by Effector Th1 CD4 + T Cells: A Critical Mechanism for Protection from Severe Immunopathology during Malaria Infection This information is current as of September 28, 2021. Ana Paula Freitas do Rosário, Tracey Lamb, Philip Spence, Robin Stephens, Agathe Lang, Axel Roers, Werner Muller, Anne O'Garra and Jean Langhorne J Immunol 2012; 188:1178-1190; Prepublished online 28 December 2011; Downloaded from doi: 10.4049/jimmunol.1102755 http://www.jimmunol.org/content/188/3/1178 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2011/12/29/jimmunol.110275 Material 5.DC1 References This article cites 69 articles, 29 of which you can access for free at: http://www.jimmunol.org/content/188/3/1178.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-27 Promotes IL-10 Production by Effector Th1 CD4+ T Cells: A Critical Mechanism for Protection from Severe Immunopathology during Malaria Infection Ana Paula Freitas do Rosa´rio,* Tracey Lamb,*,1 Philip Spence,* Robin Stephens,*,2 Agathe Lang,* Axel Roers,† Werner Muller,‡ Anne O’Garra,x and Jean Langhorne* Infection with the malaria parasite, Plasmodium, is characterized by excessive inflammation. The establishment of a precise balance between the pro- and anti-inflammatory responses is critical to guarantee control of the parasite and survival of the host. IL-10, a key regulatory cytokine produced by many cells of the immune system, has been shown to protect mice against pathology during acute Plasmodium chabaudi chabaudi AS model of malaria. However, the critical cellular source of IL-10 is still unknown. In this article, we demonstrate that T cell-derived IL-10 is necessary for the control of pathology during acute malaria, as mice bearing Downloaded from specific deletion of Il10 in T cells fully reproduce the phenotype observed in Il102/2 mice, with significant weight loss, decline in temperature, and increased mortality. Furthermore, we show that IFN-g+ Th1 cells are the main producers of IL-10 throughout acute infection, expressing high levels of CD44 and ICOS, and low levels of CD127. Although Foxp3+ regulatory CD4+ T cells produce IL-10 during infection, highly activated IFN-g+ Th1 cells were shown to be the essential and sufficient source of IL-10 to guarantee protection against severe immune-mediated pathology. Finally, in this model of malaria, we demonstrate that the + + generation of protective IL10 IFN-g Th1 cells is dependent on IL-27 signaling and independent of IL-21. The Journal of http://www.jimmunol.org/ Immunology, 2012, 188: 1178–1190. he blood stages of the malaria parasite, Plasmodium, in- during infection with a variety of pathogens, including Leish- duce a proinflammatory response in the host, which al- mania spp., Candida spp., Mycobacterium tuberculosis (6), Bor- T though important for the clearance of the parasite, can detella spp. (7), and HIV (8), is detrimental, promoting pathogen lead to severe immune-mediated pathology. In humans and in survival. Conversely, the absence or low levels of IL-10 have been mice, high levels of the proinflammatory cytokines IFN-g, TNF-a, shown to correlate with severe or fatal outcome in infections with IFN-g–induced protein (IP)-10 (CXCL10), and IL-1b have been P. falciparum (9), Toxoplasma gondii (10), and Trypanosoma spp. by guest on September 28, 2021 shown to correlate with complications during malaria, such as (11). severe anemia, hypoglycemia, and cerebral malaria (1–3). IL-10 can play either a positive or negative role in protecting A successful response must strike a balance between protection the host from infectious disease or the associated immune-driven from the parasite and immunopathology, and IL-10 appears to pathology. During a blood-stage Plasmodium chabaudi chabaudi be one of the means by which this balance is established (4, 5). AS infection in mice, the requirement of this cytokine for down- Downregulation of the protective immune response by IL-10 regulating the pathology-inducing inflammatory response is evi- dent as Il102/2 mice have greater amounts of plasma IFN-g,TNF-a, *Division of Parasitology, Medical Research Council National Institute for Medical and IL-12, higher mortality, and more pronounced pathology than Research, London, NW7 1AA, United Kingdom; †Medical Faculty Carl Gustav wild-type (WT) animals (12, 13). Inactivation of IFN-g reduces Carus, University of Technology Dresden, Dresden, 01307, Germany; ‡Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, United Kingdom; the mortality (13) and pathology is ameliorated by anti–TNF-a and xDivision of Immunoregulation, Medical Research Council National Institute treatment (2), confirming that IL-10 regulation of inflammatory for Medical Research, London, United Kingdom responses is crucial in preventing severe immunopathology in this 1Current address: Division of Pediatric Infectious Diseases, Emory University School model of malaria. of Medicine, Atlanta, GA. IL-10 is produced by different immune cell types, including 2 Current address: Division of Infectious Diseases, Department of Internal Medicine, B cells, macrophages, dendritic cells (DCs) (4, 14), and several University of Texas Medical Branch, Galveston, TX. T cell subsets, such as CD8+ (15) and CD4+ T cells, including Th1 Received for publication September 22, 2011. Accepted for publication November + 27, 2011. (16, 17), Th17 (18), as well as Foxp3 regulatory T cells (Tregs) + This work was supported by the Medical Research Council United Kingdom (Med- (19) and regulatory type 1 (Tr1) cells (20). IL-10 from CD4 ical Research Council file reference U117584248) and is part of the EviMalar Eu- T cells (16), CD8+ T cells (15), and myeloid cells such as DCs ropean Network of Excellence supported by the European Union. (14) have all been shown to play important roles in regulating Address correspondence and reprint requests to Dr. Jean Langhorne, Division of immunopathology in different infection models. Furthermore, Parasitology, National Institute for Medical Research, The Ridgeway, London, + NW7 1AA, U.K. E-mail address: [email protected] within the CD4 T cell subset, IL-10 from effector (16) or Tregs The online version of this article contains supplemental material. (21) can have similar roles in different infections, or different roles Abbreviations used in this article: DC, dendritic cell; IP, IFN-g–induced protein; in the same infection. For example, in Leishmania major infec- iRBC, RBC infected with P. chabaudi chabaudi AS; MFI, mean fluorescence inten- tions, IL-10 from effector Th1 cells is necessary for suppression of sity; NIMR, National Institute for Medical Research; Tr1, regulatory type 1; Treg, inflammatory response during acute infection (16), whereas IL- regulatory T cell; WT, wild-type. 10–producing Ag-specific Foxp3+ CD4+ T cells (Tregs) suppress + Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 the clearance of the parasite by the effector CD4 T cells (21, 22). www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102755 The Journal of Immunology 1179 Despite intensive research on the mechanisms responsible for Anti–IL-10R treatment regulation of immunopathology in malaria, the cellular source of A single dose (0.82 mg/mouse) of the mAb (1B1.3) that binds specifically to protective IL-10 is not known. During P. falciparum infection, the ligand binding domain of IL-10R (42) or the IgG1 isotype control Ab greater frequencies of effector Th1 CD4+ T cells producing (GL113) (42) was injected i.p. into C57BL/6 mice 2 d after i.v. infection. IL-10 have been observed in children with uncomplicated malaria Weight loss and temperature, as well as survival rate, parasitemia, and total (23), although their protective function has not been established. numbers of iRBC, were assessed. In a mouse model of nonlethal malaria, P. yoelii, IL-10 is pri- Cell preparations marily produced early in the infection by CD4+CD252Foxp32 Single-cell suspensions obtained from spleens were incubated with FcR adaptive Tregs (24). However, a role for IL-10 from these cells block (43) followed by specific Abs (BD Pharmingen, BioLegend, or in reducing proinflammatory responses, pathology, or parasite eBioscience) using appropriate combinations of fluorochromes (FITC, PE, clearance has not been directly demonstrated. Therefore, a clear PerCP, PE Texas Red, PerCPCy5.5, PE-Cy5.5, PE-Cy7, Pacific Blue, allo- definition of the critical protective source of IL-10 during ma- phycocyanin, and allophycocyanin-Cy7): CD3 (145-2C11), CD4 (L3T4), CD8 (53-6.7), CD19 (MB19-1), NK1.1 (PK 136), CD127 (A7R34), ICOS laria infection and the mechanisms of its induction
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