Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Switzerland.
Eur J Immunol. 2012 Jul;42(7):1706-16. doi: 10.1002/eji.201142159. Epub 2012 Jun 14.
The antiretroviral drug abacavir (abc) elicits severe drug hypersensitivity reactions in HLA-B5701(+) individuals. To understand the abc-specific activation of CD8(+) T cells, we generated abc-specific T-cell clones (abc-TCCs). Abc reactivity could not be linked to the metabolism and/or processing of the drug, since abc metabolizing enzymes were not expressed in immune cells and inhibition of the proteasome in APCs did not affect TCC reactivity. Ca(2+) influx assays revealed different reactivity patterns of abc-TCCs. While all TCCs reacted to abc presented on HLA-B5701 molecules, a minority also reacted immediately to abc in solution. Titration experiments showed that the ability to react immediately to abc correlated significantly with the TCR avidity of the T cells. Modifications of soluble abc concentrations revealed that the reactivity patterns of abc-TCCs were not fixed but dynamic. When TCCs with an intermediate TCR avidity were stimulated with increasing abc concentrations, they showed an accelerated activation kinetic. Thus, they reacted immediately to the drug, similar to the reaction of TCCs of high avidity. The observed immediate activation and the noninvolvement of the proteasome suggest that, in contrast to haptens, abc-specific T-cell stimulation does not require the formation of covalent bonds to produce a neo-antigenic determinant.
抗逆转录病毒药物阿巴卡韦（abc）在 HLA-B5701(+)个体中引发严重的药物超敏反应。为了了解 abc 特异性激活 CD8(+) T 细胞的机制，我们生成了 abc 特异性 T 细胞克隆（abc-TCC）。abc 的反应性不能与药物的代谢和/或加工联系起来，因为免疫细胞中不表达 abc 代谢酶，而且 APC 中蛋白酶体的抑制作用并不影响 TCC 的反应性。Ca(2+)内流测定揭示了 abc-TCC 的不同反应模式。虽然所有 TCC 都对 HLA-B5701 分子上呈现的 abc 产生反应，但少数 TCC 也立即对溶液中的 abc 产生反应。滴定实验表明，立即对 abc 产生反应的能力与 T 细胞 TCR 的亲和力显著相关。可溶性 abc 浓度的改变表明 abc-TCC 的反应模式不是固定的，而是动态的。当具有中等 TCR 亲和力的 TCC 受到递增浓度的 abc 刺激时，它们表现出加速的激活动力学。因此，它们类似于高亲和力 TCC 的反应，立即对药物产生反应。观察到的即刻激活和蛋白酶体的不参与表明，与半抗原不同，abc 特异性 T 细胞刺激不需要形成共价键来产生新的抗原决定簇。
