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