Antiviral CD4⁺ memory T cells are IL-15 dependent

Survival and intermittent proliferation of memory CD4⁺ and CD8⁺ T cells appear to be controlled by different homeostatic mechanisms. In particular, contact with interleukin (IL)-15 has a decisive influence on memory CD8⁺ cells, but not memory CD4⁺ cells. Past studies of memory CD4⁺ cells have relied heavily on the use of naturally occurring memory phenotype (MP) cells as a surrogate for antigen (Ag)-specific memory cells. However, we show here that MP CD4⁺ cells contain a prominent subset of rapidly proliferating major histocompatibility complex (MHC) II–dependent cells. In contrast, Ag-specific memory CD4 cells have a slow turnover rate and are MHC II independent. In irradiated hosts, these latter cells ignore IL-15 and expand in response to the elevated levels of IL-7 in the lymphopenic hosts. In contrast, in normal nonlymphopenic hosts where IL-7 levels are low, memory CD4 cells are heavily dependent on IL-15. Significantly, memory CD4⁺ responsiveness to endogenous IL-15 reflects marked competition from other cells, especially CD8⁺ and natural killer cells, and increases considerably after removal of these cells. Therefore, under normal physiological conditions, homeostasis of CD8⁺ and CD4⁺ memory cells is quite similar and involves IL-15 and IL-7.