Published online April 7, 2008
doi:10.1084/jem.20071258
The Journal of Experimental Medicine, Vol. 205, No. 4, 799-810
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Luger et al.
Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category
Dror Luger1,
Phyllis B. Silver1,
Jun Tang1,
Daniel Cua2,
Zoe Chen2,
Yoichiro Iwakura3,
Edward P. Bowman2,
Nicole M. Sgambellone2,
Chi-Chao Chan1, and
Rachel R. Caspi1
1 Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892
2 Schering-Plough/DNAX, Palo Alto, CA 94304
3 University of Tokyo, Tokyo 108-8639, Japan
CORRESPONDENCE Rachel R. Caspi: rcaspi{at}helix.nih.gov
Experimental autoimmune uveitis (EAU) represents autoimmune uveitis in humans. We examined the role of the interleukin (IL)-23–IL-17 and IL-12–T helper cell (Th)1 pathways in the pathogenesis of EAU. IL–23 but not IL-12 was necessary to elicit disease by immunization with the retinal antigen (Ag) interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant. IL-17 played a dominant role in this model; its neutralization prevented or reversed disease, and Th17 effector cells induced EAU in the absence of interferon (IFN)-
. In a transfer model, however, a polarized Th1 line could induce severe EAU independently of host IL-17. Furthermore, induction of EAU with IRBP-pulsed mature dendritic cells required generation of an IFN-–producing effector response, and an IL-17 response by itself was insufficient to elicit pathology. Finally, genetic deficiency of IL-17 did not abrogate EAU susceptibility. Thus, autoimmune pathology can develop in the context of either a Th17 or a Th1 effector response depending on the model. The data suggest that the dominant effector phenotype may be determined at least in part by conditions present during initial exposure to Ag, including the quality/quantity of Toll-like receptor stimulation and/or type of Ag-presenting cells. These data also raise the possibility that the nonredundant requirement for IL-23 in EAU may extend beyond its role in promoting the Th17 effector response and help provide a balance in the current Th1 versus Th17 paradigm.
Abbreviations used: Ag, antigen; CIA, collagen-induced arthritis; DTH, delayed-type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-binding protein; TLR, Toll-like receptor.
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