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. The cytokine interleukin 27 (IL-27), a member of the IL-12 family, is produced by cells of the innate immune system and has been shown to exert mainly suppressive effects during a wide range of inflammatory conditions, including malaria infection, where it suppresses the development of CD4⁺ T cell-dependent immunopathology. In this study we show that IL-27 suppresses the production of IFN-gamma by CD4⁺ T cells during blood stage malaria infection by preventing the development of terminally differentiated Th1 cells. We investigated the molecular mechanisms by which IL-27 inhibits the formation of terminally differentiated Th1 cells and found that it does so specifically by restricting IL-12 signals. Importantly, we demonstrate that IL-27 mediates its regulatory effects on the Th1 response through IL-10 and Foxp3⁺ regulatory T cell independent mechanisms. Thus, we have identified a new pathway though which IL-27 signalling regulates the size and quality of the Th1 response during malaria infection, which we believe will have relevance to many other pro-inflammatory conditions. Manipulation of the IL-27 pathway may therefore represent an amenable therapeutic approach during chronic inflammatory disorders.