Intracellular interaction of IL-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity

doi:10.1074/jbc.M705725200

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Intracellular interaction of IL-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity

Cristina Bergamaschi, Margherita Rosati, Rashmi Jalah, Antonio Valentin, Viraj Kulkarni, Candido Alicea, Gen-Mu Zhang, Vainav Patel, Barbara K. Felber, and George N. Pavlakis

Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702

Corresponding Author: pavlakis{at}ncifcrf.gov

We show that co-expression of interleukin 15 (IL-15) and IL-15 receptor alpha (IL-15Ra) in the same cell allows for the intracellular interaction of the two proteins early after translation resulting in increased stability and secretion of both molecules as a complex. In the absence of co-expressed IL-15Ra, a large portion of the produced IL-15 is rapidly degraded immediately after synthesis. Co-injection into mice of IL-15 and IL-15Ra expression plasmids led to significantly increased levels of the cytokine in serum as well as increased biological activity of IL-15. Examination of natural killer (NK) cells and T lymphocytes in mouse organs showed a great expansion of both cell types in the lung, liver and spleen. The presence of IL-15Ra also increased the number of CD44high memory cells with effector phenotype (CD44highCD62L-). Thus, mutual stabilization of IL-15 and IL-15Ra leads to remarkable increases in production, stability and tissue availability of bioactive IL-15 in vivo. The in vivo data show that the most potent form of IL-15 is as part of a complex with its receptor alpha either on the surface of the producing cells or as a soluble extracellular complex. These results explain the reason for co-ordinate expression of IL-15 and IL-15Ra in the same cell and suggest that the IL-15Ra is a part of the active IL-15 cytokine rather than part of the receptor.

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