Interleukin 15 and autoimmune disorders: pathophysiology, therapeutic potential, and clinical implications

Interleukin-15 (IL-15) is a pleiotropic cytokine of the common γ-chain (γc) family, playing a central role in the development, survival, and activation of natural killer (NK) cells and memory CD8⁺ T cells. Its tightly regulated expression is essential for maintaining immune homeostasis, while dysregulation of IL-15 signaling has been implicated in the pathogenesis of various autoimmune and chronic inflammatory diseases. This review explores the structural features, receptor complex, and signaling mechanisms of IL-15, emphasizing its immunomodulatory functions in both innate and adaptive immunity. We highlight the role of IL-15 in the initiation and progression of autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), type 1 diabetes, celiac disease, inflammatory bowel disease, psoriasis, and ankylosing spondylitis. Special focus is given to IL-15-mediated activation of tissue-resident memory T cells (TRM), cytotoxic CD8⁺ T cells, and NK cells, which contribute to tissue-specific autoimmunity and sustained inflammation. Furthermore, we summarize emerging therapeutic strategies targeting IL-15 and its receptor complex, including monoclonal antibodies, receptor antagonists, and cytokine fusion proteins. Clinical trials and preclinical data suggest that IL-15 blockade may offer a promising therapeutic avenue in autoimmune diseases, particularly in refractory or relapsing forms. The review concludes with future directions for integrating IL-15-targeted interventions into precision immunotherapy.