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J. Biol. Chem., Vol. 283, Issue 7, 4189-4199, February 15, 2008

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Intracellular Interaction of Interleukin-15 with Its Receptor 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. Pavlakis¹

From the Human Retrovirus Section and the Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702-1201

We show that co-expression of interleukin 15 (IL-15) and IL-15 receptor (IL-15R) 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-15R, a large portion of the produced IL-15 is rapidly degraded immediately after synthesis. Co-injection into mice of IL-15 and IL-15R 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 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-15R also increased the number of CD44^high memory cells with effector phenotype (CD44^highCD62L-). Thus, mutual stabilization of IL-15 and IL-15R 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 either on the surface of the producing cells or as a soluble extracellular complex. These results explain the reason for coordinate expression of IL-15 and IL-15R in the same cell and suggest that the IL-15R is part of the active IL-15 cytokine rather than part of the receptor.

Received for publication, July 12, 2007 , and in revised form, October 29, 2007.

^* This work was supported by the Intramural Research Program of the NCI, Center for Cancer Research, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, NCI-Frederick, Bldg. 535, Rm. 210, Frederick, MD 21702-1201. Tel.: 301-846-1474; Fax: 301-846-7146; E-mail: pavlakis{at}ncifcrf.gov.

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