IL-27 Receptor Signalling Restricts the Formation of Pathogenic, Terminally Differentiated Th1 Cells during Malaria Infection by Repressing IL-12 Dependent Signals.


Villegas-Mendez, A; de Souza, JB; Lavelle, SW; Gwyer Findlay, E; Shaw, TN; van Rooijen, N; Saris, CJ; Hunter, CA; Riley, EM; Couper, KN; (2013) IL-27 Receptor Signalling Restricts the Formation of Pathogenic, Terminally Differentiated Th1 Cells during Malaria Infection by Repressing IL-12 Dependent Signals. PLoS pathogens, 9 (4). e1003293. ISSN 1553-7366 DOI: https://doi.org/10.1371/journal.ppat.1003293

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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.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Malaria Centre
PubMed ID: 23593003
Web of Science ID: 318072700034
URI: http://researchonline.lshtm.ac.uk/id/eprint/790310

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