title: IL-27 receptor signaling regulates CD4+ T cell chemotactic responses during infection.
abstract: IL-27 exerts pleiotropic suppressive effects on naive and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4(+) T cell chemotactic responses, as a mechanism to reduce T cell-dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, proinflammatory infection, we demonstrate that IL-27R signaling represses chemotaxis of infection-derived splenic CD4(+) T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4(+) T cells from malaria-infected, IL-27R-deficient (WSX-1(-/-)) mice than from infected wild-type mice. We find that IL-27 signaling suppresses splenic CD4(+) T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4(+) T cell subtypes, including Th1 cells, and also by controlling the overall composition of the CD4(+) T cell compartment. Diminution of the Th1 response in infected WSX-1(-/-) mice in vivo by neutralization of IL-12p40 attenuated CCR5 expression by infection-derived CD4(+) T cells and also reduced splenic CD4(+) T cell chemotaxis toward CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4(+) T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Gwyer Findlay
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.forename: Colette A
authors.initials: CA
authors.lastname: Inkson
authors.forename: Tovah N
authors.initials: TN
authors.lastname: Shaw
authors.forename: Christiaan J
authors.initials: CJ
authors.lastname: Saris
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Couper
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D054407:Chemokine CCL4 / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D008288:Malaria / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010962:Plasmodium berghei / Q000276:immunology; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D018121:Receptors, Cytokine / Q000276:immunology* / Q000378:metabolism; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: C503460:Ccl5 protein, mouse; D054407:Chemokine CCL4; D018946:Chemokine CCL5; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D053762:Interleukin-12 Subunit p40; D007376:Interleukin-2; D007378:Interleukins; D019713:Receptors, CCR5; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10
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