Falk K, Rötzschke O, Strominger J L
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
Eur J Immunol. 2000 Oct;30(10):3012-20. doi: 10.1002/1521-4141(200010)30:10<3012::AID-IMMU3012>3.0.CO;2-Q.
In a previous study we reported that oligomerized T cell epitopes "superactivated" CD4+ T cells. These oligomers, consisting of 12-16 copies of a peptide epitope derived from the hemagglutinin protein of influenza virus (HA306-318), induced a specific T cell response in amounts as little as 5 pg/ml. We now show that the improved antigenicity of these multimerized epitopes can also be utilized to induce "high zone tolerance". Tolerization, similar to activation, occurred at about 3 logs lower concentration of oligomer than of peptide. HA306-318-specific T cell cultures became nonresponsive to stimulation with peptide after incubation with 0.5-5 microg/ml HA306-318 12-mer. The nonresponsiveness was accompanied by a drastic down-regulation of the TCR and by T cell elimination by apoptotic cell death. In contrast, stimulation with peptide even at 50 microg/ml led to temporary induction of anergy. Consequently, induction of tolerance with the oligomer was permanent and no recovery of the cultures was seen in recall experiments 12-14 days after high zone exposure to the 12-mer.
在之前的一项研究中，我们报道寡聚化的T细胞表位“超活化”了CD4+ T细胞。这些寡聚体由12 - 16个源自流感病毒血凝素蛋白（HA306 - 318）的肽表位拷贝组成，能以低至5 pg/ml的量诱导特异性T细胞应答。我们现在表明，这些多聚化表位增强的抗原性也可用于诱导“高区耐受”。与激活类似，耐受诱导发生时寡聚体的浓度比肽低约3个对数级。用0.5 - 5 μg/ml的HA306 - 318 12聚体孵育后，HA306 - 318特异性T细胞培养物对肽刺激不再有反应。这种无反应伴随着TCR的急剧下调以及通过凋亡性细胞死亡导致的T细胞清除。相比之下，即使在50 μg/ml的肽刺激下也只会导致暂时的无反应。因此，用寡聚体诱导的耐受是永久性的，在高区暴露于12聚体12 - 14天后的回忆实验中，未观察到培养物恢复反应。
