A pivotal role for CD40-mediated IL-6 production by dendritic cells during IL-17 induction in vivo.
The costimulatory requirements for Th17 development remain to be defined. In this study, we show that CD40-deficient animals immunized with the gram-positive bacterium Propionibacterium acnes were specifically impaired in their ability to mount an IL-17 response, but not that of IFN-gamma. The same cytokine imbalance resulted from in vivo priming with pathogen-pulsed, CD40-deficient dendritic cells (DC). Engagement of CD40 on P. acnes-conditioned DC stimulated the release of IL-12, IL-23, and IL-6, of which IL-6 alone proved essential for Th17 differentiation. Compared with wild-type DC, priming with those lacking expression of CD40 resulted in reduced disease severity during experimental autoimmune encephalomyelitis, coincident with reduced IL-17 production. Our data delineate sequential requirements for DC expression of CD40 and production of IL-6 during Th17 polarization in vitro and in vivo, and reveal distinct costimulatory requirements for Th1 vs Th17 generation.
Perona-Wright
Georgia
G
Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
Jenkins
Stephen J
SJ
O'Connor
Richard A
RA
Zienkiewicz
Dimitrios
D
McSorley
Henry J
HJ
Maizels
Rick M
RM
Anderton
Stephen M
SM
MacDonald
Andrew S
AS
D000595:Amino Acid Sequence; D000818:Animals; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011425:Propionibacterium acnes / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology
D019013:CD40 Antigens; D020381:Interleukin-17; D015850:Interleukin-6