Increased TTS abrogates IDO-mediated CD4(+) T cells suppression in patients with Graves' disease.
Indoleamine 2,3-dioxygenase (IDO)-expression in antigen-presenting cells (APCs) may control autoimmune responses by depleting the available tryptophan, whereas tryptophanyl-tRNA synthetase (TTS) may counteract this effect. The study aims to determine whether abnormal IDO and TTS activities in autoreactive T, B and dendritic cells (DCs) lead to tryptophan metabolism disorder, inducing the immune imbalance in patients with Graves' disease (GD). The concentrations of serum kynurenine and tryptophan and the mRNA expressions of IDO and TTS were analyzed, and the mixed leukocyte reaction (MLR) was employed to assess the interaction of IDO-expressing DCs and TTS-expressing CD4(+) T cells. Compared with healthy donors (HD), the ratio of serum kynurenine to tryptophan (P < 0.0001) was increased in GD patients, which was associated with the increased IDO expression in B cells (P < 0.01) and DCs (P < 0.01). GD-derived CD4(+) T cells enhanced TTS expression (P < 0.01), and its proliferation was not inhibited in the presence of IDO-expressing DCs from the GD patients. In contrast, the proliferation of HD-derived CD4(+) T cells with low TTS expression was inhibited. Increased TTS expression from CD4(+) T cells resists IDO-mediated immunosuppression from DCs, which might link to a pathogenic mechanism involved in autoreactive T cells being sustained in vivo in GD patients.
Wang
Shu
S
Department of Endocrine, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Mao
Chaoming
C
Zhao
Zefei
Z
Gu
Qiaoli
Q
Jin
Min
M
Xiao
Yichuan
Y
Jiang
Xiaohua
X
Zhao
Yongju
Y
Zhang
Yanyun
Y
Ning
Guang
G
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D007737:Kynurenine / Q000097:blood; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D014364:Tryptophan / Q000097:blood; D014369:Tryptophan-tRNA Ligase / Q000235:genetics* / Q000276:immunology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014369:Tryptophan-tRNA Ligase; C073175:WARS1 protein, human