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Synovial Autoreactive T Cells in Rheumatoid Arthritis Resist IDO-Mediated Inhibition¹

Lingqiao Zhu^*, Fang Ji^*, Yuan Wang, Yi Zhang, Qiang Liu^*,, Jingwu Z. Zhang^*,, Kouji Matsushima^¶, Qi Cao^* and Yanyun Zhang^2,*

^* Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China; Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Department of Immunology and Department of Neurology, Baylor College of Medicine, Houston, TX 77030; and ^¶ Department of Molecular Preventive Medicine, School of Medicine, the University of Tokyo, Tokyo, Japan

A hallmark of T cell-mediated autoimmunity is the persistence of autoreactive T cells. However, it remains to elucidate the manner in which synovial T cells are sustained in patients with rheumatoid arthritis (RA). We found that dendritic cells (DC) and tissues from the synovial joints of RA patients expressed higher levels of IDO than DC from healthy donors. Interestingly, T cells derived from the joint synovial fluid (SF) of RA patients proliferated in response to either autologous or allogeneic IDO-positive DC, an outcome that was not affected by the addition of IDO inhibitor 1-methyl-D-tryptophan (1-MT). In contrast, addition of 1-MT to the culture stimulated with allogeneic or autologous IDO-positive DC significantly enhanced the proliferation of T cells derived from peripheral blood of healthy donors or from peripheral blood of RA patients. Furthermore, we found that functionally active tryptophanyl-tRNA-synthetase (TTS) was significantly elevated in T cells derived from the SF of RA patients, leading to enhanced storage of tryptophan in T cells and to subsequent resistance to IDO-mediated deprivation of tryptophan. The RA SF enhancement of TTS expression in T cells was blocked by mAb to IFN- and TNF-. These results suggest that the resistance of T cells to IDO-mediated deprivation of tryptophan represents a mechanism by which autoreactive T cells are sustained in vivo in RA patients. Specifically, blocking of the up-regulation of TTS expression in T cells presents an avenue for development of a novel therapeutic approach to treatment of RA.

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 grants from Shanghai Jiao Tong University School of Medicine (211 Project); the programs of Science and Technology Commission of Shanghai Municipality (04DZ14902 and 03JC14085); Shanghai Leading Academic Discipline Project (T0206), China; Chinese Academy of Sciences (KSCX2-SW-212); Chinese Ministry of Science and Technology (863 Project 2002AA216121 and 202CCCD2000); and National Natural Science Foundation of China (NSFC30430650 and 30471593).

² Address correspondence and reprint requests to Dr. Yanyun Zhang, Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200025, China. E-mail address: yyzhang{at}sibs.ac.cn

³ Abbreviations used in this paper: RA, rheumatoid arthritis; 1-MT, 1-methyl-D-tryptophan; C_T, cycle threshold; DC, dendritic cell; PB, peripheral blood; PI, propidium iodide; SF, synovial fluid; ST, synovial tissue; TTS, tryptophanyl-tRNA-synthetase.

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