Synovial autoreactive T cells in rheumatoid arthritis resist IDO-mediated inhibition.
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-gamma and TNF-alpha. 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.
Zhu
Lingqiao
L
Joint Immunology Laboratory, Institute of Health Sciences and Shanghai Institute of Immunology, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 225 South Chongqing Road, Shanghai 200225, China.
Ji
Fang
F
Wang
Yuan
Y
Zhang
Yi
Y
Liu
Qiang
Q
Zhang
Jingwu Z
JZ
Matsushima
Kouji
K
Cao
Qi
Q
Zhang
Yanyun
Y
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D015551:Autoimmunity; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism; D014369:Tryptophan-tRNA Ligase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014364:Tryptophan; D014369:Tryptophan-tRNA Ligase