Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4(+) and CD8(+) T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4(+) T cell proliferation depended on prolonged Ag presence, whereas CD8(+) T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4(+) T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8(+) T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8(+) T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4(+) and CD8(+) T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II-restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4(+) T cells require continuous stimulation for clonal expansion, whereas CD8(+) T cells can divide following a much shorter TCR signal.