T-CELL RENEWAL RATES, TELOMERASE, AND TELOMERE LENGTH SHORTENING

Measurements on the average telomere lengths of normal human naive and memory T cells suggested that 1) naive and memory human T cells have similar division rates, and 2) that the difference between naive and m emory cells reflects the degree of clonal expansion during normal immu ne reactions, Here we develop mathematic models describing how the pop ulation average of telomere length depends on the cell division rates of naive and memory T cells during clonal expansion and normal renewal . The results show that 1) telomeres shorten with twice the cell divis ion rate, 2) that the conventional approach of estimating telomere len gth shortening per mean population doubling gives rise to estimates th at are 39% larger than the ''true'' loss per cell division, 3) that na ive and memory T cells are expected to shorten their telomeres at rate s set by the division rate of the naive T cells only, i.e., irrespecti ve of the division rate of memory T cells, 4) that the measured differ ence in the average telomere length between naive and memory T cells m ay largely reflect the difference in renewal rates between these subpo pulations rather than the clonal expansion, and 5) that full telomeras e compensation during clonal expansion is consistent with all data on the shortening of telomere length in, and between, naive and memory T cells, Thus we reconcile the apparent contradictions between the demon strated difference in division rates between human naive and memory T cells and their similar rates of telomere shortening, and the demonstr ated telomere shortening in the presence of telomerase activity.