THE PROGRESSIVE DIFFERENTIATION OF PRIMED T-CELLS IS ASSOCIATED WITH AN INCREASING SUSCEPTIBILITY TO APOPTOSIS

Recent studies have suggested that T cell memory for recall antigens r esides in clones of primed T cells with a short inter-mitotic half-lif e. In humans such cells express an isoform of the leukocyte common ant igen termed CD45RO. Nevertheless, little is known of the fate of these primed T cells after initial activation, since no markers are availab le to distinguish recently primed cells from long-established clones. This report is focused on a spectrum of primed CD4(+) T cells characte rized by an inverse relationship between the expression of two CD45 ep itopes: CD45RB and CD45RO. We show that primed CD4(+) T cells progress through many cycles of division from a CD45RB(bright)O(dull) to a CD4 5RB(dull)O(bright) state, resulting in a highly skewed distribution of the T cell receptor variable region usage within this particular popu lation. The progressive differentiation defined by the shift from CD45 RB(bright) to CD45RB(dull) 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 CD45RB(dull) cells selectively lose the capacity to synthesize interle ukin (IL)-2, a cytokine which is particularly effective in preventing T cell apoptosis, although they produce high levels of IL-4. The inabi lity to produce adequate levels of IL-2 leads to the apoptosis of prim ed CD45RB(dull) cells, when they are stimulated in the absence of exog enous IL-2. These observations show the crucial dependence of highly d ifferentiated T cells on the availability of exogenous IL-2, and sugge st both a major constraint for the persistence of T cell memory mainta ined by continually cycling primed cells, and an important mechanism c ontributing to the maintenance of T cell homeostasis in vivo.