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

PLoS Pathogens

Ana Villegas-Mendez¹  J. Brian de Souza¹  Emily Gwyer Findlay¹  Tovah N. Shaw¹  Kevin N. Couper¹  Nico van Rooijen¹  Seen-Wai Lavelle²  Christopher A. Hunter³  Christiaan J. Saris⁴  Eleanor M. Riley⁵ 

[1] Department of Immunology and Infection, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom;Department of Immunology and Molecular Pathology, University College London Medical School, London, United Kingdom;Department of Inflammation Research, Amgen, Inc., Thousand Oaks, California, United States of America;Department of Molecular Cell Biology, VU Medical Center, Amsterdam, The Netherlands;Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

关键词: T cells;    T helper cells;    Malaria;    Cell differentiation;    Plasmodium;    Regulatory T cells;    Parasitic diseases;    Cell staining;   

DOI  :  10.1371/journal.ppat.1003293

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY