Ashna Patel, Mikhail A Kutuzov, Michael L Dustin, P Anton van der Merwe, Omer Dushek
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引用次数: 0
Abstract
CD8+ T cells contribute to immune responses by producing cytokines when their T-cell receptors (TCRs) recognise peptide antigens on major-histocompability-complex class I. However, excessive cytokine production can be harmful. For example, cytokine release syndrome is a common toxicity observed in treatments that activate T cells, including chimeric antigen receptor (CAR)-T-cell therapy. While the engagement of costimulatory receptors is well known to enhance cytokine production, we have limited knowledge of their ability to regulate the kinetics of cytokine production by CAR-T cells. Here we compare early (0-12 h) and late (12-20 h) production of IFN-gg, IL-2, and TNF-a production by T cells stimulated via TCR or CARs in the presence or absence ligands for CD2, LFA-1, CD28, CD27, and 4-1BB. For T cells expressing TCRs and 1st-generation CARs, activation by antigen alone was sufficient to stimulate early cytokine production, while co-stimulation by CD2 and 4-1BB was required to maintain late cytokine production. In contrast, T cells expressing 2nd-generation CARs, which have intrinsic costimulatory signalling motifs, produce high levels of cytokines in both early and late periods in the absence of costimulatory receptor ligands. Losing the requirement for costimulation for sustained cytokine production may contribute to the effectiveness and/or toxicity of 2nd-generation CAR-T-cell therapy.
当 CD8+ T 细胞的 T 细胞受体(TCR)识别 I 类主要组织相容性复合物上的肽抗原时,会产生细胞因子,从而促进免疫反应。例如,细胞因子释放综合征是激活T细胞(包括嵌合抗原受体(CAR)-T细胞疗法)的一种常见毒性。众所周知,共价受体的参与会促进细胞因子的产生,但我们对它们调节 CAR-T 细胞产生细胞因子的动力学的能力了解有限。在这里,我们比较了在CD2、LFA-1、CD28、CD27和4-1BB配体存在或不存在的情况下,通过TCR或CAR刺激的T细胞早期(0-12小时)和晚期(12-20小时)产生的IFN-gg、IL-2和TNF-a。对于表达 TCR 和第一代 CAR 的 T 细胞,仅抗原激活就足以刺激早期细胞因子的产生,而 CD2 和 4-1BB 共同刺激才能维持晚期细胞因子的产生。相反,表达第二代 CAR 的 T 细胞具有固有的成本刺激信号基团,在没有成本刺激受体配体的情况下,在早期和晚期都能产生高水平的细胞因子。失去了持续产生细胞因子的成本刺激要求,可能会影响第二代 CAR-T 细胞疗法的有效性和/或毒性。