The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells.

We previously described unique features of the IL-15 receptor (IL-15R)alpha. IL-15Ralpha by itself forms stable complexes with IL-15 on cell surfaces and presents IL-15 in trans to neighboring natural killer/T cells. Moreover, the membrane IL-15/IL-15Ralpha complexes (membIL-15) undergo endosomal internalization but survive lysosomal degradation, allowing the complexes to recycle back to the cell surface. Here, we show that membIL-15+ cells act as a persistent source of IL-15 for the surrounding microenvironment (intercellular reservoir effect). Additionally, membIL-15+ cells give rise to augmented retention of IL-15 in the circulation as well as in tissues. Curiously, IL-15 retention was particularly associated with lungs, rather than with lymph nodes, in normal unstimulated mice, which correlated with the preferential homing of antigen-specific CD8 T cells to lungs during their contraction phase in an IL-15Ralpha-dependent manner. Furthermore, membIL-15, unlike soluble IL-15, caused sustained IL-15 signal transduction in the target cells. Collectively, these characteristics define IL-15 as a unique cytokine with prolonged in vivo survival and sustained biological action on the target cells, which may account for the proposed persistent action of IL-15 that helps the long-term survival of functional CD8 memory T cells in vivo.