CD40-CD40L cross-talk integrates strong antigenic signals and microbial stimuli to induce development of IL-17-producing CD4+ T cells.
IL-17-producing CD4(+) T cells have been recognized as key players in organ-related autoimmune disease; however, the parameters that govern their development are yet to be elucidated fully. By using both in vivo and in vitro systems, we have investigated the role of antigen dose, pathogen-associated molecular patterns, and CD40-CD40 ligand (CD40L) cross-talk in Th17 differentiation. We found that the strength of antigenic stimulation critically influenced the extent of Th17 differentiation, because high, but not low or intermediate, antigen concentrations led to IL-17 production. Strong antigenic stimulation of T cells up-regulated CD40L expression, which in concert with certain microbial stimuli (i.e., cytosine phosphate guanine, curdlan, and zymosan) synergistically increased dendritic cell (DC) IL-6 production and Th17 polarization. CD40-deficient DCs exhibited reduced cytokine release and failed to drive Th17 development in vitro. These results were confirmed in vivo where the absence of CD40-CD40L cross-talk was found to prevent the expansion of IL-17-producing cells and accordingly the development of experimental autoimmune encephalitis. Our data demonstrate that CD40-CD40L cross-talk is important for Th17 development by translating strong T cell receptor and microbial stimuli into IL-6 production.
Iezzi
Giandomenica
G
Institute of Integrative Biology, Molecular Biomedicine, ETH Zürich, Switzerland. giezzi@uhbs.ch
Sonderegger
Ivo
I
Ampenberger
Franziska
F
Schmitz
Nicole
N
Marsland
Benjamin J
BJ
Kopf
Manfred
M
D000818:Animals; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D002454:Cell Differentiation; D016764:Cell Polarity; D003713:Dendritic Cells / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis; D008089:Listeria monocytogenes / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000941:Antigens; D019013:CD40 Antigens; D053765:Interleukin-12 Subunit p35; D020381:Interleukin-17; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; D023201:CD40 Ligand