IL-7 and Not Stem Cell Factor Reverses Both the Increase in Apoptosis and the Decline in Thymopoiesis Seen in Aged Mice

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Abstract
Thymic atrophy is an age-associated decline in commitment to the T cell lineage considered to be associated with defective TCR β-chain rearrangement. 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-associated decrease in the number of CD44+CD25−CD3−CD4−CD8− cells, this study investigated whether alterations in apoptosis within the TN pathway accounted for diminishing thymocyte numbers with age. Here we show significant age-associated increases in apoptotic TN thymocytes, specifically within CD44+CD25+ and CD44−CD25+ subpopulations, known to be the location of TCR β-chain rearrangement. IL-7 added to TN cultures established from old mice significantly both reduces apoptosis and increases the percentage 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 did not improve upon IL-7 alone. IL-7R expression did not decline with age, ruling out the possibility that the age-associated increase in apoptosis was attributed to reduced IL-7R expression. Compared with PBS, treatment of old mice with IL-7 produced significant increases in live TN cells. By comparison, treatment with SCF failed to increase live TN numbers, and IL-7 and SCF together failed to significantly improve thymopoiesis above that shown by IL-7 alone. Thus, treatment with IL-7 alone can reverse the age-associated defect in TN thymocyte development revealed by in vitro studies to be located at the stages of TCR β-chain rearrangement.