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

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. © 2013 villegas-mendez et al.