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Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity [ATAC-seq]

ABSTRACT: A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhaustion T cell fates. Through multi-round in vivo CRISPR screens in chronic LCMV Clone 13 infection and transcription factor (TF) benchmarking, we identified KLF2 as a top TF driving CX3CR1⁺ effector-like exhausted cell (Texeff-like) differentiation. Overexpression of KLF2 converted CX3CR1⁻ cells into Texeff-like cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8+ T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control, but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Texeff-like program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE288039 | GEO | 2026/04/18

REPOSITORIES: GEO

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Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity [RNA-Seq]

Project description:A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhaustion T cell fates. Through multi-round in vivo CRISPR screens in chronic LCMV Clone 13 infection and transcription factor (TF) benchmarking, we identified KLF2 as a top TF driving CX3CR1⁺ effector-like exhausted cell (Texeff-like) differentiation. Overexpression of KLF2 converted CX3CR1⁻ cells into Texeff-like cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8+ T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control, but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Texeff-like program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.

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Project description:During chronic viral infection, CD8 T cells lose effector function and acquire an exhausted phenotype, a process accompanied by changes in migratory behavior and tissue residency. Exhausted CD8 T cells differentiate from stem-like progenitor (Tpro) cells into either circulating, cytotoxic effector-like (Teff) cells or tissue-resident terminally exhausted (Texh) cells. However, whether these migratory changes passively reflect cell state or actively influence exhaustion trajectories remains unclear. Here, we identify a transcriptional circuit involving Krüppel-like factor 2 (KLF2) and its homolog KLF3 that links migratory program to CD8 T cell differentiation during exhaustion. Using multi-module approaches, we show that KLF2 primarily promotes the expression and chromatin accessibility of migratory genes in Tpro and Teff subsets, while KLF3 limits these programs by repressing Klf2 transcription and competing for shared genomic binding sites. Enhancing circulation through enforced S1PR1/S1PR5 expression or CD69 deletion biases differentiation toward effector-like fates and away from terminal exhaustion, suggesting that cellular localization can influence, not just reflect, CD8 T cell fate decisions. We further describe an integrated feed-forward and feedback loop in which KLF2 induces KLF3, which in turn constrains KLF2 transcription and binding to shared genomic loci. This reciprocal regulatory circuit modulates the balance between migration and tissue residency, thereby tuning the differentiation of CD8 T cells in chronic infection. These findings provide mechanistic insight into how transcriptional regulation of migratory behavior contributes to cell fate decisions during T cell exhaustion.

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