IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals

Ana Villegas-Mendez, J Brian de Souza, Seen-Wai Lavelle, Emily Gwyer Findlay, Tovah N Shaw, Nico van Rooijen, Christiaan J Saris, Christopher A Hunter, Eleanor M Riley, Kevin N Couper

Research output: Contribution to journalArticlepeer-review

Abstract

The IL-27R, WSX-1, is required to limit IFN-γ production by effector CD4⁺ T cells in a number of different inflammatory conditions but the molecular basis of WSX-1-mediated regulation of Th1 responses in vivo during infection has not been investigated in detail. In this study we demonstrate that WSX-1 signalling suppresses the development of pathogenic, terminally differentiated (KLRG-1⁺) Th1 cells during malaria infection and establishes a restrictive threshold to constrain the emergent Th1 response. Importantly, we show that WSX-1 regulates cell-intrinsic responsiveness to IL-12 and IL-2, but the fate of the effector CD4⁺ T cell pool during malaria infection is controlled primarily through IL-12 dependent signals. Finally, we show that WSX-1 regulates Th1 cell terminal differentiation during malaria infection through IL-10 and Foxp3 independent mechanisms; the kinetics and magnitude of the Th1 response, and the degree of Th1 cell terminal differentiation, were comparable in WT, IL-10R1⁻/⁻ and IL-10⁻/⁻ mice and the numbers and phenotype of Foxp3⁺ cells were largely unaltered in WSX-1⁻/⁻ mice during infection. As expected, depletion of Foxp3⁺ cells did not enhance Th1 cell polarisation or terminal differentiation during malaria infection. Our results significantly expand our understanding of how IL-27 regulates Th1 responses in vivo during inflammatory conditions and establishes WSX-1 as a critical and non-redundant regulator of the emergent Th1 effector response during malaria infection.

Original languageEnglish
Article numbere1003293
JournalPLoS Pathogens
Volume9
Issue number4
DOIs
Publication statusPublished - 11 Apr 2013

Keywords

  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Proliferation
  • Cell Survival
  • Forkhead Transcription Factors
  • Interferon-gamma
  • Interleukin-1
  • Interleukin-10
  • Interleukin-10 Receptor alpha Subunit
  • Interleukin-12
  • Interleukin-2
  • Interleukin-27
  • Malaria, Falciparum
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Plasmodium falciparum
  • Receptors, Cytokine
  • Receptors, Immunologic
  • Signal Transduction
  • T-Box Domain Proteins
  • Th1 Cells

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