title: IL-27 receptor signalling restricts the formation of pathogenic, terminally differentiated Th1 cells during malaria infection by repressing IL-12 dependent signals.
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.
authors.affiliation: Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.forename: Seen-Wai
authors.initials: SW
authors.lastname: Lavelle
authors.forename: Emily
authors.initials: E
authors.lastname: Gwyer Findlay
authors.forename: Tovah N
authors.initials: TN
authors.lastname: Shaw
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
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; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D064094:Interleukin-27 / Q000378:metabolism; D037181:Lectins, C-Type; D016778:Malaria, Falciparum / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010963:Plasmodium falciparum / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism; D018123:Receptors, Interleukin; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C484747:Il27ra protein, mouse; D007375:Interleukin-1; D053709:Interleukin-10 Receptor alpha Subunit; D007376:Interleukin-2; D064094:Interleukin-27; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma