Ludwig Institute for Cancer Research, WELBIO and de Duve Institute, Université catholique de Louvain, B-1200 Brussels, Belgium.
TIPs, Université Libre de Bruxelles, B-1050 Brussels, Belgium.
Nat Commun. 2016 Jul 22;7:12242. doi: 10.1038/ncomms12242.
Surface galectin has been shown to contribute to dysfunctions of human tumour-infiltrating lymphocytes (TILs). We show here that galectin-covered CD8 TILs produce normal amounts of intracellular cytokines, but fail to secrete them because of defective actin rearrangements at the synapse. The non-secreting TILs also display reduced adhesion to their targets, together with defective LFA-1 recruitment and activation at the synapse. These defects are relieved by releasing surface galectin. As mild LFA-1 blockade on normal blood T cells emulate the defects of galectin-covered TILs, we conclude that galectin prevents the formation of a functional secretory synapse by preventing optimal LFA-1 triggering. Our results highlight a major secretory defect of TILs that is not revealed by widely used intracellular cytokine immunomonitoring assays. They also provide additional insights into the T-cell response, by showing that different thresholds of LFA-1 triggering are required to promote the intracellular production of cytokines and their secretion.
表面半乳糖凝集素已被证明有助于人类肿瘤浸润淋巴细胞 (TIL) 的功能障碍。我们在这里表明，被半乳糖凝集素覆盖的 CD8 TIL 会产生正常数量的细胞内细胞因子，但由于突触处的肌动蛋白重排缺陷而无法分泌它们。非分泌性 TIL 与靶细胞的黏附能力也降低，同时突触处的 LFA-1 募集和激活也存在缺陷。这些缺陷可以通过释放表面半乳糖凝集素来缓解。由于正常血液 T 细胞上的轻度 LFA-1 阻断模拟了被半乳糖凝集素覆盖的 TIL 的缺陷，我们得出结论，半乳糖凝集素通过阻止最佳 LFA-1 触发来防止功能性分泌突触的形成。我们的研究结果突出了 TIL 的一个主要分泌缺陷，这在广泛使用的细胞内细胞因子免疫监测检测中没有被揭示。它们还通过显示促进细胞内细胞因子产生及其分泌所需的不同 LFA-1 触发阈值，为 T 细胞反应提供了更多的见解。
