Tarbell Kristin V, Yamazaki Sayuri, Olson Kara, Toy Priscilla, Steinman Ralph M
Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
J Exp Med. 2004 Jun 7;199(11):1467-77. doi: 10.1084/jem.20040180.
In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet beta cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 10(5) polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.
在1型糖尿病的非肥胖糖尿病(NOD)小鼠模型中,免疫系统可识别胰岛β细胞中表达的多种自身抗原。为了抑制自身免疫,我们利用NOD小鼠的树突状细胞(DC)来扩增BDC2.5小鼠的CD25⁺ CD4⁺ 抑制性T细胞,这些T细胞对单一胰岛自身抗原具有特异性。扩增后的T细胞在体外比新鲜分离的细胞具有更强的抑制作用,这表明来自自身免疫小鼠的DC可以增加抗原特异性CD25⁺ CD4⁺ 调节性T细胞的数量和功能。重要的是,仅5000个扩增后的CD25⁺ CD4⁺ BDC2.5 T细胞就能阻断NOD小鼠中致糖尿病T细胞引起的自身免疫,而来自NOD小鼠的10⁵个多克隆CD25⁺ CD4⁺ T细胞则无活性。当对治疗后的小鼠胰岛进行检查时,在早期(3周)而非后期(11周)时间点,胰岛炎的发展被阻断。即使在致糖尿病T细胞注射14天后给予扩增后的CD25⁺ CD4⁺ BDC2.5 T细胞,它们仍然有效。我们的数据表明,DC可以产生在体内抑制自身免疫疾病的CD25⁺ CD4⁺ T细胞。这可能会成为免疫治疗的一条新途径,特别是因为对单一自身抗原产生反应的CD25⁺ CD4⁺ 调节性细胞可以抑制由对多种抗原的反应性介导的糖尿病。