Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug
Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug
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DOI：
10.1172/jci35017
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发表时间：
2008-07-01
影响因子：
15.9
通讯作者：
Gribben, John G.
中科院分区：
文献类型：
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作者：
Ramsay, Alan G.;Johnson, Amy J.;Gribben, John G.
癌症与免疫缺陷有关，但其生物学基础尚不明确。在这里，我们证明受损的肌动蛋白聚合导致慢性淋巴细胞白血病（CLL）患者的CD4（+）和CD8（+）T细胞与APC的免疫突触形成缺陷。虽然这种突触功能障碍部分是由于CLL细胞具有较差的APC功能，但在CLL患者的T细胞中也鉴定出有缺陷的肌动蛋白聚合。我们进一步证明，与CLL细胞接触后，在健康的同种异体T细胞中诱导免疫突触形成缺陷。这需要直接接触，并通过阻断CLL B细胞上的粘附分子来抑制。在来自CLL患者的T细胞和来自与CLL细胞接触的健康个体的T细胞中，关键调节蛋白向免疫突触的募集被抑制。用免疫调节药物来那度胺治疗自体T细胞和CLL细胞导致突触形成的改善。这些结果定义了我们认为是CLL患者T细胞中的一种新型免疫功能障碍，对自体和同种异体免疫治疗方法都有影响，并将免疫突触缺陷的修复确定为改善癌症免疫治疗方法的重要步骤。
Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4(+) and CD8(+) T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.