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- Title
IL-27 Receptor Signalling Restricts the Formation of Pathogenic, Terminally Differentiated Th1 Cells during Malaria Infection by Repressing IL-12 Dependent Signals.
- Authors
Villegas-Mendez, Ana; de Souza, J. Brian; Lavelle, Seen-Wai; Findlay, Emily Gwyer; Shaw, Tovah N.; van Rooijen, Nico; Saris, Christiaan J.; Hunter, Christopher A.; Riley, Eleanor M.; Couper, Kevin N.
- 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.
- Subjects
INTERLEUKIN-27; INTERLEUKINS; PATHOGENIC microorganisms; MICROORGANISMS; CELLS
- Publication
PLoS Pathogens, 2013, Vol 9, Issue 4, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1003293