Differentiation and Persistence of Memory CD8 + T Cells Depend on T Cell Factor 1

T cell factor 1 (TCF-1) is a transcription factor known to act downstream of the canonical Wnt pathway and is essential for normal T cell development. However, its physiological roles in mature CD8 + T cell responses are unknown. Here we showed that TCF-1 deficiency limited proliferation of CD8 + effector T cells and impaired their differentiation toward a central memory phenotype. Moreover, TCF-1-deficient memory CD8 + T cells were progressively lost over time, exhibiting reduced expression of the antiapoptotic molecule Bcl-2 and interleukin-2 receptor β chain and diminished IL-15-driven proliferation. TCF-1 was directly associated with the Eomes allele and the Wnt-TCF-1 pathway was necessary and sufficient for optimal Eomes expression in naive and memory CD8 + T cells. Importantly, forced expression of Eomes partly protected TCF-1-deficient memory CD8 + T cells from time-dependent attrition. Our studies thus identify TCF-1 as a critical player in a transcriptional program that regulates memory CD8 differentiation and longevity. [Display omitted] ► TCF-1 is required for expansion of primary and secondary effector CD8 + T cells ► TCF-1 deficiency impairs differentiation of central memory CD8 + T cells ► TCF-1 has a nonredundant role in long-term persistence of memory CD8 + T cells ► Wnt-TCF-1 pathway acts upstream of eomesodermin in memory CD8 + T cells