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Dryad

KLF2 maintains lineage fidelity and suppresses CD8 T cell exhaustion during acute LCMV infection (PerturbSeq Data)

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Nov 12, 2024 version files 290.85 GB

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Abstract

Naïve CD8 T cells have the potential to differentiate into a variety of functional states during an immune response. How these developmental decisions are made and what mechanisms exist to suppress differentiation towards alternative fates remains unclear. We employed in vivo CRISPR/Cas9-based perturbation sequencing to assess the role of ~40 transcription factors (TFs) and epigenetic modulators (EMs) in T cell fate decisions. Unexpectedly, we found that knockout of 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 TBET to drive effector differentiation. KLF2 was also necessary to maintain tumor-specific progenitor-exhausted T cells. Thus, KLF2 provides effector CD8 T cell lineage fidelity and suppresses the exhaustion program.