Emerging roles for IL-15 in the activation and function of T-cells during immune stimulation

Interleukin (IL)-15 is a cytokine that promotes the development and homeostasis of a group of lymphocytes; however, IL-15 is also significantly upregulated in response to pathogen infections and in autoimmune diseases. With its ability to promote T-cell proliferation and survival and influence migration and effector functions, elevated IL-15 can impact T-cell responses in numerous ways. Nonetheless, the importance of IL-15 during early infection and autoimmunity is unclear. Furthermore, the mechanisms regulating IL-15 responses in both inflammatory situations and during the steady state are still being elucidated. The mechanisms by which IL-15 mediate responses are unique among cytokines. IL-15 associates with IL-15R alpha within cells where it can either be transpresented to neighboring cells or cleaved into a soluble cytokine/receptor complex. Increased production of soluble (s) IL-15Ra/IL-15 complexes is seen upon different types of immune stimulation, suggesting that these are circumstance when sIL-15 complexes are most likely to act. How common this response is remains unclear, as the production of sIL-15 complexes has only been recently appreciated. This review sets out to emphasize how IL-15 is frequently increased in response to pathogen infections and during autoimmunity and inflammatory conditions. Since pathogen infections and inflammatory diseases share signaling pathways that induce sIL-15 complexes, including pattern recognition receptors and type I interferon, sIL-15 complexes may be generated in more situations than realized. While there are multiple cellular targets of IL-15, this review primarily focuses on how T-cells are likely affected by IL-15 during immune activation and describes evidence for the aforementioned activities. Some of these responses include effects on T-cell proliferation, survival, metabolism, trafficking, and effector functions. Lastly, potential and current therapies that regulate IL-15-mediated responses during infections, autoimmunity, and cancer are discussed. Overall, IL-15 is a not just a factor promoting the differentiation and homeostasis of memory CD8 T-cells, but it is an important immune modulator acting in many circumstances involving immune stimulation and activation.