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Abstract：
Introduction: B lymphocyte-induced maturation protein 1 (BLIMP1) encoded by the positive regulatory domain 1 gene (PRDM1), is a key regulator in T cell differentiation in mouse models. BLIMP1-deficiency results in a lower effector phenotype and a higher memory phenotype. Methods: In this study, we aimed to determine the role of transcription factor BLIMP1 in human T cell differentiation. Specifically, we investigated the role of BLIMP1 in memory differentiation and exhaustion of human T cells. We used CRISPR interference (CRISPRi) to knock-down BLIMP1 and investigated the differential expressions of T cell memory and exhaustion markers in BLIMP1-deficient T cells in comparison with BLIMP1-sufficient ex vivo expanded human T cells. Results: BLIMP1-deficiency caused an increase in central memory (CM) T cells and a decrease in effector memory (EM) T cells. There was a decrease in the amount of TIM3 exhaustion marker expression in BLIMP1-deficient T cells; however, there was an increase in PD1 exhaustion marker expression in BLIMP1-deficient T cells compared with BLIMP1-sufficient T cells. Conclusion: Our study provides the first functional evidence of the impact of BLIMP1 on the regulation of human T cell memory and exhaustion phenotype. These findings suggest that BLIMP1 may be a promising target to improve the immune response in adoptive T cell therapy settings.
摘要：
简介：B淋巴细胞诱导成熟蛋白1（BLIMP1）编码的正调节域1基因（PRDM1），是小鼠模型中T细胞分化的关键调节因子。BLIMP1缺乏导致较低的效应子表型和较高的记忆表型。方法:在本研究中,我们旨在确定转录因子BLIMP1在人T细胞分化中的作用。具体来说,我们研究了BLIMP1在人类T细胞记忆分化和耗尽中的作用。我们使用CRISPR干扰（CRISPRi）敲低BLIMP1，并与BLIMP1充足的离体扩增的人T细胞相比，研究了BLIMP1缺陷型T细胞中T细胞记忆和耗尽标志物的差异表达。结果：BLIMP1缺陷导致中枢记忆（CM）T细胞增加和效应记忆（EM）T细胞减少。BLIMP1缺陷型T细胞中TIM3耗竭标记表达量减少；然而，与BLIMP1充足的T细胞相比,BLIMP1缺陷型T细胞中PD1耗尽标记表达增加.结论：我们的研究提供了BLIMP1对人T细胞记忆和耗尽表型调节的影响的第一个功能证据。这些发现表明BLIMP1可能是改善过继性T细胞治疗环境中的免疫应答的有希望的靶标。
