KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection

• 成果类型: Article
• 署名作者: Fagerberg, Eric; Attanasio, John; Dien, Christine; Singh, Jaiveer; Kessler, Emily A.; Abdullah, Leena; Shen, Jian; Hunt, Brian G.; Connolly, Kelli A.; De Brouwer, Edward; He, Jiaming; Iyer, Nivedita R.; Buck, Jessica; Borr, Emily R.; Damo, Martina; Foster, Gena G.; Giles, Josephine R.; Huang, Yina H.; Tsang, John S.; Krishnaswamy, Smita; Cui, Weiguo; Joshi, Nikhil S.
• 署名单位: Yale University; Yale University; Dartmouth College; Northwestern University; Feinberg School of Medicine; Yale University; University of Chicago; Yale University; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Yale University; Chan Zuckerberg Initiative (CZI); Yale University; Yale University; Yale University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11376
• DOI: 10.1126/science.adn2337
• 发表日期: 2025-02-14
• 页码: 736-+
• 关键词: kruppel-like factor-2; transcriptional signature; terminal differentiation; effector; expression; contraction; transitions; persistence; TRAFFICKING; generation

摘要

Naive CD8 T cells have the potential to differentiate into a spectrum of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation toward alternative fates remains unclear. We employed in vivo CRISPR-Cas9-based perturbation sequencing to assess the role of similar to 40 transcription factors (TFs) and epigenetic modulators in T cell fate decisions. Unexpectedly, we found that knockout of the TF Klf2 resulted in aberrant differentiation to exhausted-like CD8 T cells during acute infection. KLF2 was required to suppress the exhaustion-promoting TF TOX and to enable the TF TBET to drive effector differentiation. KLF2 was also necessary to maintain a polyfunctional tumor-specific progenitor state. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.