Rescue of T cell exhaustion by ingenol mebutate. Rescue of T cell exhaustion by ingenol mebutate

Inhibitory receptors (IR) and inhibitory ligands function as critical regulators of immune responses by tempering T cell activity to microbial infections and cancers. In humans, several types of persisting viruses such as HIV, HBV and HCV, as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. By screening a collection of bioactive small molecules, we identified and validated compounds that restore cytokine production and enhance proliferation of exhausted T cells. Analysis of our top hit ingenol mebutate, a protein kinase C inducing diterpene ester, revealed a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Overall design: exhausted virus-specific CD8+ T cells cultured with ingenol mebutate or vehicle

抑制性受体（inhibitory receptors, IR）与抑制性配体通过抑制T细胞针对微生物感染及癌症的活性，成为免疫应答的关键调控因子。在人类体内，多种持续性病毒（如人类免疫缺陷病毒HIV、乙型肝炎病毒HBV与丙型肝炎病毒HCV）以及各类癌症，可通过上调抑制性配体激活IR信号通路，最终抑制T细胞功能（即T细胞耗竭），使得病原体或肿瘤逃避免疫监视，进而导致疾病持续进展。本研究通过筛选一系列生物活性小分子，鉴定并验证了可恢复耗竭T细胞细胞因子产生能力、促进其增殖的化合物。对筛选得到的最优候选化合物巨大戟醇甲基丁烯酸酯（ingenol mebutate，一种可诱导蛋白激酶C激活的二萜酯类化合物）进行分析后发现，该分子能够阻断T细胞上由IR信号通路介导的抑制性信号级联反应。实验整体设计：将病毒特异性耗竭CD8+ T细胞分别与巨大戟醇甲基丁烯酸酯或溶剂对照进行培养。