Investigating the biology of IL-15 and IL-15/IL-15Ralpha

IL-15 plays a multifaceted role in the development and maintenance of the immune system and is an attractive therapeutic target for the treatment of tumors and intracellular infections, such as viruses. The current data illustrate that IL-15 is not secreted, but rather associates intracellularly with IL-15Rα and is transpresented on a cell\u27s surface to apposing cells that minimally express the shared IL-2Rβγ. This mechanism of action, along with other regulatory factors, has made it difficult to detect IL-15 protein and has important implications when utilizing IL-15 as a therapeutic. The work presented in this thesis has three main points. Firstly, we illustrate that administering IL-15 precomplexed to sIL-15Rα enhances IL-15 activity in vivo by increasing IL-15 half-life and bioavailability, as well as forcing IL-15 transpresentation. Interestingly, IL-15/sIL-15Rα treatment can stimulate tumor rejection better than IL-15 alone. Secondly, we also demonstrate that although naïve CD8 T cells appear nonresponsive to IL-15 alone in vivo they can respond vigorously to IL-15/sIL-15Rα in a MHC class I dependent manner, proliferating and acquiring effector function. A naïve CD8 T cell\u27s degree of responsiveness to IL-15/sIL-15Rα is dependent on its avidity for MHC class I; thus, not all endogenous naïve CD8 T cells have the same potential to respond to IL-15 complex, highlighting important therapeutic implications. Finally, using a novel BAC-IL-15 EmGFP mouse model we describe the expression of IL-15 in the immune system, identifying novel IL-15 expressers and a previously unappreciated variation within dendritic cell populations. Furthermore, we note that IL-15 induction in response to viral infection is very quick and short-lived and surprisingly dependent on type I IFN. The data presented in this work furthers our understanding of general IL-15 biology and its potential as an immune-base therapeutic.