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G. Shi, B. P. Vistica, C.-R. Yu, C. A. Cox, V. Montalvo, E. F. Wawrousek, C. E. Egwuagu, I. Gery; Pertussis Toxin (PTX) is Superior to Other Toll-Like Receptor (TLR) Ligands in Shifting T-helper (Th) Cell Populations Towards Th17. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2832.
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In a previous study, we showed that PTX is superior to other TLR ligands in enhancing pathogenic autoimmunity (Fujimoto et al, J Immunol, 2006). The underlying mechanism of PTX in this disease process is not entirely clear. Here, we have investigated the potential role of Th17, a newly defined immunopathogenic Th lymphocyte lineage, in this process.
Naive CD4+ cells from mice expressing hen egg lysozyme (HEL)-specific T cell receptor were adoptively transferred into recipient mice expressing HEL in their lens. Various TLR ligands, including PTX, LPS, poly (I:C) and CpG oligodeoxynucleotide, were injected into recipient mice on the following day. Recipient eyes were collected one week post-ligand injection, and inflammatory changes were determined by histological examination. Intraocular levels of IL-17, IFN-g and IL-22 mRNA transcripts were measured by real-time PCR. Inflammatory cells were isolated from recipient eyes and both intracellular IL-17 and IFN-g expression were determined by flow cytometry.
Histological analysis indicated that treatment with PTX triggered the most severe inflammation in recipient mouse eyes. Intraocular transcript levels of both IL-17 and IL-22 mRNA were found to be significantly higher in the PTX-treated group. IFN-g levels were also found to be higher, but to a lesser extent than IL-17 and IL-22. Flow cytometric analysis of cells from recipient eyes showed: (1) Th17 cell numbers were ~5 fold higher than Th1 cells in the PTX-treated group, ~2 fold higher in the LPS-treated group and approximately equal in the poly(I:C)-treated group, whereas Th1 cell numbers were ~2 fold higher than Th17 cells in the CPG-treated group. (2) TLR ligands are capable of driving differentiation of both recipient and donor naive CD4+ cells to Th1 cells, but they drove only eye infiltrating donor naive CD4+ cells to differentiate into Th17.
The superiority of PTX over other TLR ligands in triggering pathogenic autoimmunity is due in part to its unique capability to shift the Th population towards Th17. These findings suggest that Th17 may play a dominant role in the immunopathogenic process initiated by PTX, although Th1 cells likely contribute to this process as well.
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