Ca2+ Release from the Endoplasmic Reticulum of NY-ESO-1-Specific T Cells Is Modulated by the Affinity of TCR and by the Use of the CD8 Coreceptor
Ca2+ Release from the Endoplasmic Reticulum of NY-ESO-1-Specific T Cells Is Modulated by the Affinity of TCR and by the Use of the CD8 Coreceptor
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DOI：
10.4049/jimmunol.0902103
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发表时间：
2010-02-15
影响因子：
4.4
通讯作者：
Cerundolo, Vincenzo
中科院分区：
文献类型：
--
作者：
Chen, Ji-Li;Morgan, Anthony J.;Cerundolo, Vincenzo
尽管几种癌症免疫治疗策略是基于使用类似肽和调节过继转移的T细胞的TCR亲和力，目前尚不清楚强和弱TCR刺激引起的肿瘤特异性T细胞活化是否引起来自细胞内Ca 2+储存的不同Ca 2+特征，以及从内质网（ER）释放Ca 2+的幅度是否可以通过与肽/MHC结合的辅助受体进一步调节。在这项研究中，我们结合了功能、结构和动力学测量，以关联由对肿瘤表位NY-ESO-1特异性的1G 4 T细胞克隆的刺激触发的Ca 2+信号的强度（157-165）。NY-ESO-1（157-165）肽的两种类似物对HLA-A2分子具有相似的亲和力，但对1G 4 TCR的结合亲和力相差6倍，导致不同的Ca 2+信号和T细胞活化。1G 4刺激的更强的刺激清空ER的存储Ca 2+，即使在没有CD 8结合，导致持续的Ca 2+流入。与此相反，较弱的刺激只引起部分排空存储的Ca 2+，导致显着减少和振荡的Ca 2+信号，这是由CD 8结合增强。我们的数据定义的范围内的TCR/肽MHC的亲和力需要诱导消耗的Ca 2+从细胞内的商店和提供的洞察能力的T细胞定制使用的CD 8辅助受体，以提高Ca 2+从ER释放。这反过来又调节来自细胞外环境的Ca 2+流入，最终控制T细胞活化。免疫学杂志，2010，184：1829-1839。
Although several cancer immunotherapy strategies are based on the use of analog peptides and on the modulation of the TCR affinity of adoptively transferred T cells, it remains unclear whether tumor-specific T cell activation by strong and weak TCR stimuli evoke different Ca2+ signatures from the Ca2+ intracellular stores and whether the amplitude of Ca2+ release from the endoplasmic reticulum (ER) can be further modulated by coreceptor binding to peptide/MHC. In this study, we combined functional, structural, and kinetic measurements to correlate the intensity of Ca2+ signals triggered by the stimulation of the 1G4 T cell clone specific to the tumor epitope NY-ESO-1(157-165). Two analogs of the NY-ESO-1(157-165) peptide, having similar affinity to HLA-A2 molecules, but a 6-fold difference in binding affinity for the 1G4 TCR, resulted in different Ca2+ signals and T cell activation. 1G4 stimulation by the stronger stimulus emptied the ER of stored Ca2+, even in the absence of CD8 binding, resulting in sustained Ca2+ influx. In contrast, the weaker stimulus induced only partial emptying of stored Ca2+, resulting in significantly diminished and oscillatory Ca2+ signals, which were enhanced by CD8 binding. Our data define the range of TCR/peptide MHC affinities required to induce depletion of Ca2+ from intracellular stores and provide insights into the ability of T cells to tailor the use of the CD8 coreceptor to enhance Ca2+ release from the ER. This, in turn, modulates Ca2+ influx from the extracellular environment, ultimately controlling T cell activation. The Journal of Immunology, 2010, 184: 1829-1839.