Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes
Suppression of autoimmune disease after vaccination with autoreactive T cells that express Qa-1 peptide complexes
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DOI：
10.1172/jci200420772
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发表时间：
2004-04-01
影响因子：
15.9
通讯作者：
Cantor, H
中科院分区：
文献类型：
--
作者：
Panoutsakopoulou, V;Huster, KM;Cantor, H
自身反应性T细胞引起自身免疫性疾病的能力是有据可查的。用减毒的自身反应性T细胞（T细胞疫苗接种，或TCV）免疫可以诱导T细胞依赖性的自身免疫应答抑制的发现已经打开了调节性T细胞可以被利用来抑制自身免疫疾病的可能性。然而，TCV的临床应用进展缓慢，部分原因是其潜在机制仍不确定。我们研究了TCV诱导的两种小鼠自身免疫模型的疾病抵抗的分子基础：单纯疱疹病毒-1（科斯株）诱导的疱疹性角膜基质炎和非肥胖糖尿病（NOD）小鼠的小鼠自身免疫性糖尿病。我们发现TCV的治疗效果依赖于抑制性CD 8细胞的激活，这些细胞特异性识别自身反应性CD 4细胞表达的Qa-1结合肽。我们阐明了Qa-1和自身肽之间的分子相互作用，该肽产生能够诱导抑制性CD 8细胞并将其靶向自身反应性CD 4细胞的生物活性配体。这些研究表明，疫苗接种肽脉冲细胞轴承人类相当于鼠Qa-1（HLA-E）可能是一种方便和有效的临床方法，细胞治疗自身免疫性疾病。
The ability of autoreactive T cells to provoke autoimmune disease is well documented. The finding that immunization with attenuated autoreactive T cells (T cell vaccination, or TCV) can induce T cell-dependent inhibition of autoimmune responses has opened the possibility that regulatory T cells may be harnessed to inhibit autoimmune disease. Progress in the clinical application of TCV, however, has been slow, in part because the underlying mechanism has remained clouded in uncertainty. We have investigated the molecular basis of TCV-induced disease resistance in two murine models of autoimmunity: herpes simplex virus-1 (KOS strain)-induced herpes stromal keratitis and murine autoimmune diabetes in non-obese diabetic (NOD) mice. We find that the therapeutic effects of TCV depend on activation of suppressive CD8 cells that specifically recognize Qa-1-bound peptides expressed by autoreactive CD4 cells. We clarify the molecular interaction between Qa-1 and self peptides that generates biologically active ligands capable of both inducing suppressive CD8 cells and targeting them to autoreactive CD4 cells. These studies suggest that vaccination with peptide-pulsed cells bearing the human equivalent of murine Qa-1 (HLA-E) may represent a convenient and effective clinical approach to cellular therapy of autoimmune disease.