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Pertussis Toxin Is Superior to TLR Ligands in Enhancing Pathogenic Autoimmunity, Targeted at a Neo-Self Antigen, by Triggering Robust Expansion of Th1 Cells and Their Cytokine Production¹

Chiaki Fujimoto^*, Cheng-Rong Yu^2,*, Guangpu Shi^2,*, Barbara P. Vistica^*, Eric F. Wawrousek, Dennis M. Klinman, Chi-Chao Chan^*, Charles E. Egwuagu^* and Igal Gery^3,*

^* Laboratory of Immunology and Laboratory of Molecular and Developmental Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; and Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892

Microbial products are assumed to play a major role in triggering pathogenic autoimmunity. Recently accumulated data have shown that these products stimulate the immune system by interacting with TLRs, expressed on APCs. To examine the capacity of various TLR ligands to trigger pathogenic autoimmunity, we used a system in which naive CD4 cells, specific against hen egg lysozyme (HEL), are injected into recipient mice expressing HEL in their eyes. Only when stimulated, the naive cells acquire pathogenic capacity and induce ocular inflammation. Seven TLR ligands were tested in this system: lipoteichoic acid/peptidoglycan, zymosan, poly (I:C), LPS, pertussis toxin (PTX), flagellin, and CpG oligodeoxynucleotide. Treatment of recipient mice with HEL alone stimulated proliferation of the transferred cells, but no disease, whereas ocular inflammation did develop in recipient mice coinjected with HEL and any one of the seven TLR ligands. Inflammation induced by PTX surpassed by its severity those induced by all other tested TLR ligands and was accompanied by a dramatic increase in number of the transferred cells that acquired features of effector Th1 lymphocytes. Ocular inflammation and number of transferred cells in recipients injected with PTX and HEL were substantially reduced by treatment with Abs against IFN- or IL-12, thus indicating the role of these cytokines in the PTX effect. Overall, our observations demonstrate that various TLR ligands are capable of triggering pathogenic autoimmunity and that PTX surpasses other microbial products in this activity, by stimulating excessive proliferation and polarization toward Th1 of naive T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health.

² C.-R.Y. and G.S. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Igal Gery, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Building 10, Room 10N208, Bethesda, MD 20892-1857. E-mail address: geryi{at}nei.nih.gov

⁴ Abbreviations used in this paper: PGN, peptidoglycan; LTA, lipoteichoic acid; ODN, oligodeoxynucleotide; PTX, pertussis toxin; poly(I:C), polyriboinosinic polyribocytidylic acid; Tg, transgenic; ALPC, allophycocyanin; HEL, hen egg lysozyme; EAU, experimental autoimmune uveitis.

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