IL-7 and not stem cell Factor Reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice

Thymic atrophy is an age-associated decline in commitment to the T cell lin eage considered to be associated with defective TCR beta -chain rearrangeme nt. Both IL-7 and stem cell factor (SCF) have dominant roles at this stage of triple negative (TN) thymocyte development. Because there is no age-asso ciated decrease in the number of CD44(+)CD25(-)CD3(-)CD4(-)CD8(-) cells, th is study investigated whether alterations in apoptosis within the TN pathwa y accounted for diminishing thymocyte numbers with age. Here we show signif icant age-associated increases in apoptotic TN thymocytes, specifically wit hin CD44(+)CD25(+) and CD44(-)CD25(+) subpopulations, known to be the locat ion of TCR P-chain rearrangement. IL-7 added to TN cultures established fro m old mice significantly both reduces apoptosis and increases the percentag e of live cells within CD44+CD25+ and CD44-CD25+ subpopulations after 24 h, with prosurvival effects remaining after 5 days. SCF failed to demonstrate prosurvival effects in old or young cultures, and IL-7 and SCF together di d not improve upon IL-7 alone. IL-7R expression did not decline with age, r uling out the possibility that the age-associated increase in apoptosis was attributed to reduced IL-7R expression. Compared with PBS, treatment of ol d mice with IL-7 produced significant increases in live TN cells. By compar ison, treatment with SCF failed to Increase live TN numbers, and IL-7 and S CF together failed to significantly improve thymopoiesis above that shown b y IL-7 alone. Thus, treatment with IL-7 alone can reverse the age-associate d defect in TN thymocyte development revealed by in vitro studies to be loc ated at the stages of TCR beta -chain rearrangement.