Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8(+)T cells, natural killer (NK) cells, innate lymphoid cells, macrophages and dendritic cells. IL-15 is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoimmune type 1 diabetes (T1D). IL-15 receptor (IL-15R) consists of a specific a chain, the beta chain that is shared with IL-2R and the common gamma chain. IL-15 is unique in the manner in which it binds and signals through its receptor subunits. IL-15 that is complexed with IL-15Ra binds to the beta gamma receptor complex present on the responding cell to mediate its biological effects through a process referred to as trans-presentation. The trans-presented IL-15 is essential to mediate the biological effects on T lymphocytes and NK cells. Here we show that IL-15, but not IL-15Ra, is required for the development of spontaneous and virus-induced T1D, viral clearance and for antigen cross-presentation to CD8(+) T lymphocytes. Our findings provide insight into the complexities of IL-15 signalling in the initiation and maintenance of CD8(+) T cell-mediated immune responses.