Recent studies have suggested that T cell memory for recall antigens resides in clones of primed T cells with a short inter-mitotic half-life. In humans such cells express an isoform of the leukocyte common antigen termed CD45RO. Nevertheless, little is known of the fate of these primed T cells after initial activation, since no markers are available to distinguish recently primed cells from long-established clones. This report is focused on a spectrum of primed CD4+ T cells characterized by an inverse relationship between the expression of two CD45 epitopes: CD45RB and CD45RO. We show that primed CD4+ T cells progress through many cycles of division from a CD45RBbrightOdull to a CD45RBdullObright state, resulting in a highly skewed distribution of the T cell receptor variable region usage within this particular population. The progressive differentiation defined by the shift from CD45RBbright to CD45RBdull is paralleled by the gradual loss of bcl-2 and gain of Fas expression, two features associated with an increased propensity for apoptosis. At the same time, the highly differentiated CD45RBdull cells selectively lose the capacity to synthesize interleukin (IL)-2, a cytokine which is particularly effective in preventing T cell apoptosis, although they produce high levels of IL-4. The inability to produce adequate levels of IL-2 leads to the apoptosis of primed CD45RBdull cells, when they are stimulated in the absence of exogenous IL-2. These observations show the crucial dependence of highly differentiated T cells on the availability of exogenous IL-2, and suggest both a major constraint for the persistence of T cell memory maintained by continually cycling primed cells, and an important mechanism contributing to the maintenance of T cell homeostasis in vivo.