STAT5/Runx3 axis mediates cytotoxic activity in CD4+ T cells during early neuroinflammation

CD4+ T cells are crucial for the development of autoimmune neuroinflammation in mice and are widely held to orchestrate the inflammatory cascade and immunopathology. Here, we show that auto-aggressive CD4⁺ T cells acquire a cytotoxic phenotype (CD4-CTL) and function during the early phase of relapsing-remitting multiple sclerosis (RRMS) and in experimental autoimmune encephalomyelitis (EAE). We identify the enhanced activation of the STAT5–Runx3 axis as a key driver of CD4-CTL development and maintenance. Notably, cytotoxic activity becomes more pronounced once these cells infiltrate the central nervous system (CNS). Importantly, a cytotoxic signature in peripheral CD4⁺ T cells reliably distinguishes early-stage RRMS patients from healthy controls. Mechanistically, CD4-CTLs share core molecular programs with effector CD8⁺ T cells. Together, our findings reveal potential biomarkers for early multiple sclerosis (MS) diagnosis, tools for monitoring treatment response, and targets for novel therapeutic strategies