The homeostatic maintenance of memory T cells constitutes the cellular basis of immunological memory. Memory CD8+ T cells proliferate to maintain lineages of antigen specific T cells for months or years, thereby protecting hosts against recurrent infections with microbial pathogens such as viruses. Recent studies from our lab indicate that IL-15 and its high affinity receptor IL-15Ra are essential for the proliferative maintenance of these cells. Surprisingly, we found that IL-15Ra expression on RAG-1 independent hematopoietic cells (i.e., accessory cells), rather than CD8+ T cells, support memory CD8+ T cells. We have also shown that these accessory cells use IL-15Ra to trans-present IL-15 to IL-2/15RP expressing CD8+ T cells in vivo. Finally, our most recent studies suggest that IL-15 and IL-15Ra need to be coordinately expressed by the same accessory cells to trans-present IL-15 to memory CD8+ T cells. These surprising findings prompt us to consider an entirely new cell biological mechanism for IL-15Ra's actions. Specifically, IL-15 may not be a secreted, soluble cytokine under physiological conditions. Rather, IL-15 and IL-15Ra may associate with each other within accessory cells and emerge on the cell surface to transpresent IL-15 to memory CD8+ T cells. Thus, we may need to think about IL-15 and IL-15Ra as a cell surface bound ligand, more similar to a co-stimulatory molecule. To test this hypothesis, we propose to: (1) determine the specific cell types that use IL-15Ra to support memory CD8+ T cells in vivo;(2) determine the intracellular kinetics and association of IL-15Ra and IL-15 in accessory cells;and (3) determine the structural requirements of IL-15Ra important for supporting memory CD8+ T cell homeostasis in vivo. These experiments should reveal novel insights into the cellular and cell biological mechanisms by which IL-15Ra supports lymphoid homeostasis in vivo. The immunological importance of our studies is threefold. First, they redefine the physiological concept of """"""""homeostatic space,"""""""" which can now be refocused upon cells that bear IL-15Ra and support memory CD8+T cells through """"""""trans-presentation."""""""" Secondly, our studies provide the first evidence that IL-15/IL-15Ra complexes on the surface of accessory cells may function as surface bound ligands, indicating that memory CD8+ T cells must make intimate contact with IL-15Ra expressing accessory cells for their homeostasis. Thirdly, they suggest that IL-15 may bind to IL-15Ra prior to exiting accessory cells, raising entirely novel concepts about cytokine biology. Our studies are highly relevant to the regulation of the duration of immune responses, and to immunological memory. Future attempts to either enhance antiviral vaccine effectiveness or to suppress persistent inflammation in autoimmune conditions may benefit greatly from the mechanistic insights we are gaining into IL-15 biology.
