The extent of cell division that occurs in vivo in normal lymphoid cells is not well characterized. Similarly, the remaining capacity for cell replication of normal and abnormal lymphocytes is incompletely characterized. Because these represent critical parameters of lymphocyte biology, the replicative history and the residual replicative potential of human naive and memory T cells have been analyzed. Telomeres are unique terminal chromosomal structures whose length decreases with cell division in vitro and with increased age in vivo for human somatic cells. We assessed telomere length as a measure of the in vivo replicative history of naive and memory human T cells, and found that telomeric terminal restriction fragments were 1.4 plus minus 0.1 kb longer in CD4+ naive T cells than in memory cells from the same donors, a relationship that remained constant over a wide range of donor age. These findings suggest that the differentiation of memory cells from naive precursors occurs with substantial clonal expansion and that the magnitude of this expansion is, on average, similar over a wide range of age. In addition, when replicative potential was assessed in vitro, it was found that the capacity of naive cells for cell division was 128-fold greater as measured in mean population doublings than the capacity of memory cells from the same individuals. Human CD4+ naive and memory cells thus differ in in vivo replicative history as reflected in telomeric length as well as in their residual replicative capacity. These relationships may be significant for pathologies such as HIV infection, in which CD4+ T cell generation may be compromised, and for therapeutic interventions in which gene transfer or immunotherapy is mediated by cells whose in vivo expansion is essential for therapeutic effect.
