IL-27 receptor signaling regulates CD4+ T cell chemotactic responses during infection

Emily Gwyer Findlay, Ana Villegas-Mendez, J Brian de Souza, Colette A Inkson, Tovah N Shaw, Christiaan J Saris, Christopher A Hunter, Eleanor M Riley, Kevin N Couper

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4553-61
Number of pages9
JournalJournal of Immunology
Volume190
Issue number9
DOIs
Publication statusPublished - 1 May 2013

Keywords

  • Animals
  • CD4-Positive T-Lymphocytes
  • Chemokine CCL4
  • Chemokine CCL5
  • Inflammation
  • Interleukin-12 Subunit p40
  • Interleukin-2
  • Interleukins
  • Malaria
  • Mice
  • Mice, Inbred C57BL
  • Plasmodium berghei
  • Receptors, CCR5
  • Receptors, Cytokine
  • Receptors, Interleukin-10
  • Signal Transduction
  • Th1 Cells

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