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Priming of naïve CD8+ T cells requires three signals: 1) cognate antigen, 2) co-stimulation, and 3) cytokines. These signals orchestrate CD8+ T cell differentiation. Particularly, strong T cell receptor (TCR) signals induce a more robust effector response, while weak TCR signals preferentially favor memory CD8+ T cells. However, memory cells induced upon varied TCR signaling strengths have been reported to be functionally similar. In this work, we show that, in contrast to this assumption, the strength of T cell receptor (TCR) signaling determines the requirement for interleukin-2 (IL-2) signals to form a pool of memory CD8+ T cells that are functionally different. We found that upon secondary antigen encounter, memory CD8+ T cells induced upon priming with lower TCR and IL-2 signals exhibited delayed cell cycle entry, impaired expansion and intracellular calcium accumulation compared to those primed with …