Proposed model for IL-15 function in vivo. (A) At the steady state, T-cell subpopulations traffic between the blood and peripheral tissues (black arrows), and their number is kept constant through homeostatic mechanisms (curved arrows). Almost all over the body, CD4⁺ T cells outnumber CD8⁺ T cells. (B) Early after IL-15 treatment, trafficking from blood to tissues is altered, and lymphopenia is observed as a consequence of lymphocyte retention in the peripheral tissues (left black arrow). IL-15 greatly increases lymphocyte, especially memory T-cell, cycling (curved arrows), which are activated and express Ki-67. At this time, CD8⁺ (light and dark green circles) greatly outnumber CD4⁺ (orange and red circles) T cells. However, IL-15 treatment does not alter the balance of naive and memory T cells in peripheral tissues. Activated lymphocytes are then released into the circulation (right black arrow) and account for the increased lymphocyte count in the blood and for the reduced naive/memory ratio in both CD4⁺ and CD8⁺ T cells. It is like that the increased tendency to undergo apoptosis results from the massive stimulation of these cells or to the withdrawal of cytokine after therapy. (C) After IL-15 treatments were stopped, lymphocyte subpopulation counts are quickly restored in the peripheral blood, probably due to the migration to extra-lymphoid sites. However, the proportion of memory T-cell subsets in blood and tissues are normalized as well, thus suggesting the nonpersistence of expanded cells in the body. Activation and proliferation are dampened, but CD8⁺ still outnumber CD4⁺ T cells in the LNs but not in other tissues.