title: Parasite-Specific CD4+ IFN-γ+ IL-10+ T Cells Distribute within Both Lymphoid and Nonlymphoid Compartments and Are Controlled Systemically by Interleukin-27 and ICOS during Blood-Stage Malaria Infection.
abstract: Immune-mediated pathology in interleukin-10 (IL-10)-deficient mice during blood-stage malaria infection typically manifests in nonlymphoid organs, such as the liver and lung. Thus, it is critical to define the cellular sources of IL-10 in these sensitive nonlymphoid compartments during infection. Moreover, it is important to determine if IL-10 production is controlled through conserved or disparate molecular programs in distinct anatomical locations during malaria infection, as this may enable spatiotemporal tuning of the regulatory immune response. In this study, using dual gamma interferon (IFN-γ)-yellow fluorescent protein (YFP) and IL-10-green fluorescent protein (GFP) reporter mice, we show that CD4(+) YFP(+) T cells are the major source of IL-10 in both lymphoid and nonlymphoid compartments throughout the course of blood-stage Plasmodium yoelii infection. Mature splenic CD4(+) YFP(+) GFP(+) T cells, which preferentially expressed high levels of CCR5, were capable of migrating to and seeding the nonlymphoid tissues, indicating that the systemically distributed host-protective cells have a common developmental history. Despite exhibiting comparable phenotypes, CD4(+) YFP(+) GFP(+) T cells from the liver and lung produced significantly larger quantities of IL-10 than their splenic counterparts, showing that the CD4(+) YFP(+) GFP(+) T cells exert graded functions in distinct tissue locations during infection. Unexpectedly, given the unique environmental conditions within discrete nonlymphoid and lymphoid organs, we show that IL-10 production by CD4(+) YFP(+) T cells is controlled systemically during malaria infection through IL-27 receptor signaling that is supported after CD4(+) T cell priming by ICOS signaling. The results in this study substantially improve our understanding of the systemic IL-10 response to malaria infection, particularly within sensitive nonlymphoid organs.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Tovah N
authors.initials: TN
authors.lastname: Shaw
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Colette A
authors.initials: CA
authors.lastname: Inkson
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Strangward
authors.affiliation: Institute of Immunity and Transplantation, UCL Department of Immunology, Royal Free Hospital, London, United Kingdom.
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom kevin.couper@manchester.ac.uk.
authors.forename: Kevin N
authors.identifier: http://orcid.org/0000-0003-4659-8960
authors.initials: KN
authors.lastname: Couper
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D049452:Green Fluorescent Proteins / Q000235:genetics; D060889:Inducible T-Cell Co-Stimulator Protein / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D008099:Liver / Q000276:immunology; D008164:Luminescent Proteins / Q000235:genetics; D008168:Lung / Q000276:immunology; D008288:Malaria / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010967:Plasmodium yoelii / Q000276:immunology; D013154:Spleen / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; C556062:IL10 protein, mouse; C556694:Icos protein, mouse; C486767:Il27 protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma