LEF1 and niche factors determine T cell stemness across chronic diseases.

Abstract

In settings of persistent (self or foreign) antigen, such as autoimmunity and chronic infection, immune responses are sustained by stem-like T cells. Although TCF1 has emerged as a key transcription factor (TF) associated with stemness, the TCF1^hi population is heterogeneous, raising the question of whether TCF1 exclusively defines the stem T cell (T_SC) pool. Using preclinical models of autoimmune type 1 diabetes and chronic infection, we discover that a small subset of TCF1^hi T cells express the TF LEF1. LEF1⁺ TCF1^hi T cells define a true self-renewing T_SC pool. T_SC give rise to LEF1^- TCF1^hi progenitor T cells (T_PRO), which lack stem functions and generate terminally differentiated TCF1^lo T cells (T_DIFF) (T_SC→T_PRO→T_DIFF). We show that LEF1 is essential for T cell stemness. Autoimmune and exhausted LEF1⁺ T_SC share a unique epigenetically encoded core program enriched for genes and pathways characteristic of embryonic and adult stem cells, including WNT/β-catenin and Notch signaling. Spatial positioning, niche signals, and migration regulate stem-cell fate; accordingly, targeting integrins or Notch signaling impairs T cell stemness and prevents disease. Our studies identify LEF1 and niche-derived factors as fundamental regulators of T cell stemness across chronic diseases.