美国宾夕法尼亚大学史俊炜和E. John Wherry研究组合作取得最新进展。他们表明体内CD8 + T细胞CRISPR筛选揭示了Fli1在感染和癌症中的控制。这一研究成果发表在2021年2月25日出版的国际学术期刊《细胞》上。
他们开发了体内T细胞CRISPR筛选平台，并确定了通过ETS家族转录因子（TFs） 、Fli1抑制效应T细胞（TEFF）生物学的关键机制。Fli1的基因敲除增强了TEFF反应，而不会损害记忆或衰竭的前体。Fli1通过与效应子相关基因的顺式调控元件结合来抑制TEFF谱系分化。Fli1的丢失增加了ETS：RUNX基序上的染色质可及性，从而使Runx3驱动的TEFF生物学效率更高。
缺乏Fli1的CD8 + T细胞提供了更好的针对多种感染和肿瘤的保护作用。这些数据表明Fli1可以保护CD8 + T细胞的转录环境免受过度的ETS：RUNX驱动的TEFF细胞分化的影响。此外，Fli1的基因缺失可改善TEFF分化和感染和癌症中的保护性免疫。
据悉，改善抗原特异性T细胞的效应子活性是癌症免疫治疗的主要目标。尽管确定了几个TEFF驱动TF，TEFF生物学的转录协调仍然知之甚少。
附：英文原文
Title: In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer
Author: Zeyu Chen, Eri Arai, Omar Khan, Zhen Zhang, Shin Foong Ngiow, Yuan He, Hua Huang, Sasikanth Manne, Zhendong Cao, Amy E. Baxter, Zhangying Cai, Elizabeth Freilich, Mohammed A. Ali, Josephine R. Giles, Jennifer E. Wu, Allison R. Greenplate, Mohamed A. Hakeem, Qingzhou Chen, Makoto Kurachi, Kito Nzingha, Viktoriya Ekshyyan, Divij Mathew, Zhuoyu Wen, Nancy A. Speck, Alexis Battle, Shelley L. Berger, E. John Wherry, Junwei Shi
Issue&Volume: 2021-02-25
Abstract: Improving effector activity of antigen-specific T cells is a major goal in cancerimmunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatinaccessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infectionsand tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.
DOI: 10.1016/j.cell.2021.02.019
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00169-0