Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh, United Kingdom.
J Immunol. 2010 Dec 1;185(11):6545-54. doi: 10.4049/jimmunol.1001867. Epub 2010 Nov 3.
The effect of TCR signals on the differentiation of memory T cells is poorly defined. Conventional wisdom suggests that high-avidity interactions are best for the selection of vaccine Ag candidates or T cell specificities for adoptive T cell therapy to stimulate robust responses. However, in conditions of Ag persistence, high-avidity clones might exhaust and fail to form long-lived protective memory. We have manipulated the functional avidity of CD4 T cells by reducing expression of Lck, a key kinase involved in TCR triggering. Using a mouse model, we followed tetramer-positive T cells responding to a tumor Ag expressed by an adenocarcinoma. We show that reducing the functional avidity increased effector-effector memory responses and improved the generation of self-renewing, recirculating, tumor Ag-specific memory phenotype CD4 T cells. Moreover, such cells together with wild type CD8 T cells were better able to control tumor growth. Mechanistically, reducing Lck prolonged IL-2 production and cell turnover in the central memory population while reducing expression of exhaustion markers in the face of chronic Ag. Our data indicate that, in situations of persistent Ag challenge, generating T cells with reduced functional avidity may elicit more effective immune responses.
TCR 信号对记忆 T 细胞分化的影响尚未明确。传统观点认为，高亲和力相互作用最有利于疫苗抗原候选物或 T 细胞特异性的选择，以刺激强烈的反应，用于过继性 T 细胞治疗。然而，在抗原持续存在的情况下，高亲和力克隆可能会耗尽，无法形成长期保护性记忆。我们通过降低参与 TCR 触发的关键激酶 Lck 的表达来操纵 CD4 T 细胞的功能亲和力。我们使用一种小鼠模型，对表达腺癌的肿瘤抗原做出反应的四聚体阳性 T 细胞进行了跟踪。结果表明，降低功能亲和力可增加效应器记忆反应，并改善自我更新、循环、肿瘤抗原特异性记忆表型 CD4 T 细胞的产生。此外，此类细胞与野生型 CD8 T 细胞一起能够更好地控制肿瘤生长。从机制上讲，降低 Lck 可延长中央记忆群体中 IL-2 的产生和细胞更新，同时在面对慢性抗原时减少衰竭标志物的表达。我们的数据表明，在持续抗原挑战的情况下，产生功能亲和力降低的 T 细胞可能会引发更有效的免疫反应。
