Wang Su He, Chen Gwo-Hsiao, Fan Yongyi, Van Antwerp Mary, Baker James R
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-2200, USA.
Endocrinology. 2009 Apr;150(4):2000-7. doi: 10.1210/en.2008-1389. Epub 2008 Nov 13.
There have been several reports that TNF-related apoptosis-inducing ligand (TRAIL) has the ability to suppress the development of experimental autoimmune diseases, including a mouse model of experimental autoimmune encephalomyelitis, a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus, in mice and experimental autoimmune thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examined TRAIL effects on CD4(+)CD25(+) regulatory T cells. CD4(+)CD25(+) T cells prepared from mouse thyroglobulin (mTg)-immunized CBA/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4(+)CD25(+) T cells included both CD4(+)CD25(+)CD45RB(Low) (regulatory) and CD4(+)CD25(+)CD45RB(High) (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4(+)CD25(+)CD45RB(Low) T cells compared with mice immunized with mTg alone. CD4(+)CD25(+)CD45RB(Low) T cells expressed much higher levels of the forkhead family transcription factor, IL-10, and TGFbeta1 than CD4(+)CD25(+)CD45RB(High) T cells, and these cells can completely suppress the proliferation of the mTg-primed splenocytes in lower concentrations than the unfractionated CD4(+)CD25(+) T cells. Furthermore, transfer of these cells into CBA/J mice prior to mTg-primed splenocyte injection could markedly reduce the frequency and severity of EAT development. CD4(+)CD25(+)CD45RB(Low) T cells were more effective at suppressing histological thyroiditis than unfractionated cells. These results indicated that TRAIL can increase the number of mTg-specific CD4(+)CD25(+)CD45RB(Low) T cells, inhibiting autoimmune responses and preventing the progression of EAT. These findings reveal a novel mechanism by which TRAIL could inhibit autoimmune disease.
已有多项报道称，肿瘤坏死因子相关凋亡诱导配体（TRAIL）具有抑制实验性自身免疫性疾病发展的能力，这些疾病包括实验性自身免疫性脑脊髓炎小鼠模型、类风湿性关节炎兔模型、小鼠1型糖尿病以及小鼠实验性自身免疫性甲状腺炎（EAT）。然而，TRAIL作用的潜在机制尚未明确。在本研究中，我们专门研究了TRAIL对CD4(+)CD25(+)调节性T细胞的作用。从小鼠甲状腺球蛋白（mTg）免疫的CBA/J小鼠制备的CD4(+)CD25(+) T细胞，在体外与TRAIL和树突状细胞共同存在的情况下能够增殖。这些CD4(+)CD25(+) T细胞包括CD4(+)CD25(+)CD45RB(Low)（调节性）和CD4(+)CD25(+)CD45RB(High)（效应性）T细胞。我们的结果表明，与仅用mTg免疫的小鼠相比，用TRAIL处理的mTg免疫小鼠的CD4(+)CD25(+)CD45RB(Low) T细胞数量显著增加。CD4(+)CD25(+)CD45RB(Low) T细胞比CD4(+)CD25(+)CD45RB(High) T细胞表达更高水平的叉头家族转录因子、白细胞介素-10和转化生长因子β1，并且这些细胞能够以低于未分离的CD4(+)CD25(+) T细胞的浓度完全抑制mTg致敏脾细胞的增殖。此外，在注射mTg致敏脾细胞之前将这些细胞转移到CBA/J小鼠体内，可显著降低EAT发生的频率和严重程度。CD4(+)CD25(+)CD45RB(Low) T细胞在抑制组织学甲状腺炎方面比未分离的细胞更有效。这些结果表明，TRAIL可增加mTg特异性CD4(+)CD25(+)CD45RB(Low) T细胞的数量，抑制自身免疫反应并阻止EAT的进展。这些发现揭示了TRAIL抑制自身免疫性疾病的一种新机制。
