The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation

IL-15 is critical for natural killer (NK)–cell development and function and for memory CD8+ T-cell homeostasis. The IL-15 receptor consists of IL-15Rα, IL-2Rβ, and the common cytokine receptor γ chain (γc). IL-15Rα is known to “trans-present” IL-15 to an IL-2Rβ/γc heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Rα cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Rα and intracellular domain of IL-2Rα (IL-15Rαext/IL-2Rαint) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8+ T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15–induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Rα expression, indicating a signaling role for the IL-15Rα cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Rα and IL-15Rα cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Rαext/IL-2Rαint receptor still supports trans-presentation. These experiments collectively indicate that IL-15Rα can act in cis in addition to acting in trans to present IL-15 to responding cells.