The IL-15 receptor chain cytoplasmic domain is critical for normal IL-15R 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-15R , IL-2R , and the common cytokine receptor chain ( c). IL-15R is known to “trans-present” IL-15 to an IL-2R / c heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15R cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15R and intracellular domain of IL-2R (IL-15R ext/IL-2R int) 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 wildtype (WT) transfectants with similar levels of IL-15R expression, indicating a signaling role for the IL-15R cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2R and IL-15R cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15R ext/ IL-2R int receptor still supports transpresentation. These experiments collectively indicate that IL-15R can act in cis in addition to acting in trans to present IL-15 to responding cells. (Blood. 2008;112: 4411-4419)