HLA Haplotype Determines Hapten or p-i T Cell Reactivity to Flucloxacillin
HLA Haplotype Determines Hapten or p-i T Cell Reactivity to Flucloxacillin
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DOI：
10.4049/jimmunol.1202949
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发表时间：
2013-05-15
影响因子：
4.4
通讯作者：
Yerly, Daniel
中科院分区：
文献类型：
--
作者：
Wuillemin, Natascha;Adam, Jacqueline;Yerly, Daniel
药物性肝损伤（DILI）是药物戒断的主要原因。一个特别有趣的例子是氟氯西林（FLUX）DILI，它与HLA-B*57:01等位基因有关。目前，FLUX-DILI的机制尚不清楚，但HLA相关性提示活化T细胞在肝损伤的病理机制中起作用。为了了解FLUX、HLA分子和T细胞之间的相互作用，我们从FLUX-naive HLA- b *57: 01（+）和HLA- b *57: 01（-）健康供体中生成了FLUX反应的T细胞，并研究了T细胞刺激的机制。我们发现FLUX以两种不同的方式刺激CD8(+) T细胞。一方面，FLUX稳定地存在于各种HLA分子上，抵抗广泛的洗涤，依赖于蛋白酶体加工，提示其半抗原机制。另一方面，在HLA-B* 57:01（+）个体中，我们观察到与免疫受体（p-i）为基础的T细胞反应性的药理学相互作用。FLUX以一种不稳定的方式呈现，其进一步的特征是蛋白酶体加工的独立性和在溶液中受到FLUX刺激后立即激活T细胞克隆。这种基于p-i的T细胞刺激仅限于HLA-B* 57:01等位基因。我们得出结论，HLA-B* 57:01的存在驱动CD8(+) T细胞对青霉素衍生物FLUX的非半抗原机制的反应。
Drug-induced liver injury (DILI) is a main cause of drug withdrawal. A particularly interesting example is flucloxacillin (FLUX)DILI, which is associated with the HLA-B*57:01 allele. At present, the mechanism of FLUX-DILI is not understood, but the HLA association suggests a role for activated T cells in the pathomechanism of liver damage. To understand the interaction among FLUX, HLA molecules, and T cells, we generated FLUX-reacting T cells from FLUX-naive HLA-B*57: 01(+) and HLA-B*57: 01(-) healthy donors and investigated the mechanism of T cell stimulation. We found that FLUX stimulates CD8(+) T cells in two distinct manners. On one hand, FLUX was stably presented on various HLA molecules, resistant to extensive washing and dependent on proteasomal processing, suggesting a hapten mechanism. On the other hand, in HLA-B*57: 01(+) individuals, we observed a pharmacological interaction with immune receptors (p-i)-based T cell reactivity. FLUX was presented in a labile manner that was further characterized by independence of proteasomal processing and immediate T cell clone activation upon stimulation with FLUX in solution. This p-i-based T cell stimulation was restricted to the HLA-B*57: 01 allele. We conclude that the presence of HLA-B*57: 01 drives CD8(+) T cell responses to the penicillin-derivative FLUX toward nonhapten mechanism.