J Immunol 2003 May 1;170(9):4802-4809
Ito A, Matejuk A, Hopke C, Drought H, Dwyer J, Zamora A, Subramanian S, Vandenbark AA, Offner H.
Department of Experimental Pathology, Institute for Medical Sciences, Kyoto University, Kyoto, Japan. Department of Neurology, Oregon Health and Science University, Portland, OR 97201. Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97201. L. Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland. Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97201.
The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG(35-55)).
MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients.
However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients.
Coculture of T cells with IL-12 enhanced the secretion of IFN-gamma, but not TNF-alpha, whereas coculture with IL-18 enhanced the secretion of TNF-alpha, but not INF-gamma.
However, coculture with both IL-18 and IL-12 induced high levels of both TNF-alpha and IFN-gamma.
Additionally, IL-12 selectively enhanced mRNA expression of CCR5, whereas IL-18 selectively enhanced the expression of CCR4 and CCR7, and CCR4 and CCR5 were coexpressed on the surface of T cells cocultured with IL-12 and IL-18.
Finally, estrogen treatment, previously found to inhibit both TNF-alpha and IFN-gamma production, completely abrogated all signs of passive EAE.
These data demonstrate that optimal potentiation of encephalitogenic activity can be achieved by conditioning MOG-specific T cells with the combination of IL-12 and IL-18, which, respectively, induce the secretion of IFN-gamma/CCR5 and TNF-alpha/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.