The impact of KLF2-KLF3 regulated cellular localization on exhausted T cell differentiation [CUT&Tag]

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.