Abstract Poorly functional effector CD8 T cells are generated in some pathological situations, including responses to weakly antigenic tumors. To identify the molecular bases for such defective differentiation, we monitored gene expression in naive monoclonal CD8 T cells during responses to TCR ligands of different affinity. We further evaluated whether responses to weak Ags may be improved by addition of cytokines. Transient gene expression was observed for a cluster of genes in response to the weak TCR agonist. Strikingly, gene expression was stabilized by low dose IL-2. This IL-2-sustained gene cluster encoded notably transcripts for CD25, cytolytic effector molecules (granzyme B) and TNF-R family costimulatory molecules (glucocorticoid-induced TNF-R (GITR), OX40, and 4-1BB). IL-2-enhanced surface expression or function was also demonstrated in vivo for these genes. A constitutive active form of STAT5 mimicked the IL-2 effect by sustaining transcripts for the same gene cluster. Consistent with this, under conditions of low avidity TCR engagement and IL-2 treatment, endogenous STAT5 binding to 4-1BB and granzyme B promoters was demonstrated by chromatin immunoprecipitation. This study highlights those genes for which IL-2, via STAT5 activation, acts as a stabilizer of gene regulation initiated by TCR signals, contributing to the development of a complete CD8 T cell effector program.