Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death.
Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death.
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DOI：
10.1158/0008-5472.can-09-1176
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发表时间：
2009-08-01
期刊：
影响因子：
11.2
通讯作者：
Mehrotra S
中科院分区：
文献类型：
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作者：
Norell H;Martins da Palma T;Lesher A;Kaur N;Mehrotra M;Naga OS;Spivey N;Olafimihan S;Chakraborty NG;Voelkel-Johnson C;Nishimura MI;Mukherji B;Mehrotra S
溶细胞性T淋巴细胞（CTL）在适当的抗原刺激下经历大量扩增。体内平衡是由这些细胞随后的“收缩”来维持的。活化诱导的细胞死亡（AICD）和程序性细胞死亡防止了由活化的CTL的过量和延长的持续性引起的不良副作用，所述活化的CTL在不受控制和/或持续扩增时发生。然而，效应细胞持久性已被确定为成功的T细胞介导的过继免疫治疗的标志。因此，预防AICD可能是取得更成功的临床结果的关键。我们先前已经表明，用c-jun N-末端激酶（JNK）抑制剂SP 600125处理，保护人黑素瘤表位Mart-127-35反应性CTL在再次遇到同源抗原时免于凋亡死亡。然而，JNK的抑制也干扰CTL分泌干扰素（IFN）-γ的功能能力。在这里，我们表明，活性氧类（ROS）抑制剂，如超氧化物歧化酶模拟物，锰（III）四（5，10，15，20-苯甲酸）卟啉（MnTBAP），有效地保护Mart-127-35反应性初级CTL从AICD，而不损害他们的功能能力。MnTBAP防止了在遇到同源抗原时在对照处理的细胞中观察到的细胞内ROS、线粒体膜塌陷和DNA片段化的增加。此外，在初级CTL中预防AICD的机制包括阻断JNK活化。最后，临床上用于癌症免疫治疗的肿瘤反应性体外扩增的肿瘤浸润淋巴细胞也受益于MnTBAP介导的抗氧化剂治疗。因此，氧化还原途径的调节可能改善CTL持久性，并导致基于T细胞的免疫疗法的更好的临床结果。
Cytolytic T lymphocytes (CTL) undergo massive expansion upon appropriate antigenic stimulation. Homeostasis is maintained by a subsequent “contraction” of these cells. Activation-induced cell death (AICD) and programmed cell death, prevent the untoward side effects arising from excessive numbers and prolonged persistence of activated CTL that occur upon uncontrolled and/or continued expansion. However, effector cell persistence has been identified as a hallmark of successful T cell-mediated adoptive immunotherapy. Thus, prevention of AICD may be critical to achieve more successful clinical results. We have previously shown that treatment with c-jun N-terminal kinase (JNK)-inhibitor, SP600125, protects human melanoma epitope Mart-127-35 reactive CTL from apoptotic death upon their re-encounter with cognate antigen. However, inhibition of JNK also interferes with the functional capability of the CTL to secrete interferon (IFN)-γ. Here, we show that reactive oxygen species (ROS) inhibitors such as the superoxide dismutase mimetic, Mn (III) tetrakis (5, 10, 15, 20-benzoic acid) porphyrin (MnTBAP), efficiently protected Mart-127-35 reactive primary CTL from AICD without impairing their functional capability. MnTBAP prevented the increase in intracellular ROS, mitochondrial membrane collapse, and DNA fragmentation observed in control treated cells upon cognate antigen encounter. Furthermore, the mechanism of AICD prevention in primary CTL included blockade of JNK activation. Finally, tumor reactive in vitro expanded tumor infiltrating lymphocytes, which are used clinically in cancer immunotherapy, also benefit from MnTBAP mediated antioxidant treatment. Thus, modulation of the redox pathway might improve CTL persistence and lead to better clinical results for T cell-based immunotherapies.