Kong Ning, Lan Qin, Chen Maogen, Wang Julie, Shi Wei, Horwitz David A, Quesniaux Valerie, Ryffel Bernhard, Liu Zhongmin, Brand David, Zou Hejian, Zheng Song Guo
University of Southern California, Los Angeles, CA 90033, USA.
Arthritis Rheum. 2012 Aug;64(8):2548-58. doi: 10.1002/art.34513.
Transferred CD4+CD25+FoxP3+ Treg cells can prevent autoimmune disease, but generally fail to ameliorate established disease. This study was undertaken to compare the effects of antigen-specific Treg cells induced with interleukin-2 (IL-2) and transforming growth factor β (TGFβ) ex vivo (induced Treg [iTreg] cells) to the effects of equivalent expanded thymus-derived natural Treg (nTreg) cells on established collagen-induced arthritis (CIA).
CIA was induced in DBA/1 mice by immunization with type II collagen (CII), and before or shortly after immunization, mice were treated with iTreg or nTreg cells that were generated or expanded in vitro. Clinical scores were determined. Inflammatory responses were determined by measuring the levels of anti-CII antibody in the serum and examining the histologic features of the mouse joints. The Th1/Th17-mediated autoreactive response was evaluated by determining the cytokine profile of the draining lymph node (LN) cells of the mice by flow cytometry.
Following transfer, nTreg cells exhibited decreased FoxP3 and Bcl-2 expression and decreased suppressive activity, and many converted to Th17 cells. In contrast, transferred iTreg cells were more numerous, retained FoxP3 expression and their suppressive activity in the presence of IL-6, and were resistant to Th17 conversion. Notably, 10 days after the transfer of donor iTreg cells, predominance was shifted from Th17 cells to Treg cells in the draining LNs of recipient mice.
These findings provide evidence that transferred TGFβ-induced iTreg cells are more stable and functional than nTreg cells in mice with established autoimmunity. Moreover, iTreg cells can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of human iTreg cells in subjects with chronic, immune-mediated inflammatory diseases should be investigated.
转移的CD4+CD25+FoxP3+调节性T细胞（Treg细胞）可预防自身免疫性疾病，但通常无法改善已确诊的疾病。本研究旨在比较体外经白细胞介素-2（IL-2）和转化生长因子β（TGFβ）诱导的抗原特异性Treg细胞（诱导性Treg [iTreg]细胞）与等量扩增的胸腺来源天然Treg（nTreg）细胞对已确诊的胶原诱导性关节炎（CIA）的影响。
用II型胶原（CII）免疫DBA/1小鼠诱导CIA，在免疫前或免疫后不久，用体外产生或扩增的iTreg或nTreg细胞治疗小鼠。测定临床评分。通过测量血清中抗CII抗体水平并检查小鼠关节的组织学特征来确定炎症反应。通过流式细胞术测定小鼠引流淋巴结（LN）细胞的细胞因子谱，评估Th1/Th17介导的自身反应性应答。
转移后，nTreg细胞表现出FoxP3和Bcl-2表达降低以及抑制活性降低，许多细胞转化为Th17细胞。相比之下，转移的iTreg细胞数量更多，在IL-6存在的情况下保留FoxP3表达及其抑制活性，并且对Th17转化具有抗性。值得注意的是，在供体iTreg细胞转移10天后，受体小鼠引流淋巴结中Th17细胞占主导地位转变为Treg细胞占主导地位。
这些发现提供了证据，表明在已建立自身免疫的小鼠中，转移的TGFβ诱导的iTreg细胞比nTreg细胞更稳定且功能更强。此外，即使在存在持续炎症的情况下，iTreg细胞也可具有致耐受性作用。应研究人iTreg细胞在慢性免疫介导炎症性疾病患者中的治疗潜力。
