Krüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration.

During chronic viral infection, CD8(+) progenitor exhausted T (Tpro) cells give rise to either cytotoxic effector-like exhausted T (Teff) cells that are migratory or terminally exhausted T cells (Texh) that reside in the tissue parenchyma. Here, we explored how cellular localization influences exhausted T cell fate. We found that Krüppel-like factor 2 (KLF2) promoted the expression and chromatin accessibility of migratory genes, whereas its counterpart, KLF3, limited these programs and promoted tissue residency. Forcing CD8(+) T cells out of the tissue environment biased differentiation from the Texh toward the Teff cell trajectory, suggesting that cellular localization can actively influence cell-fate decisions. Mechanistically, KLF2 induced KLF3, which, in turn, constrained Klf2 transcription and competed for shared chromatin-binding sites. In summary, KLF2 and KLF3 form a reciprocal regulatory circuit that governs CD8(+) T cell migration and exhaustion during chronic viral infection.