The Journal of Experimental Medicine
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Published 3 January 2005. doi:10.1084/jem.20041057
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 1, 139-148
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ARTICLE

 Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function

Rong Zeng1, Rosanne Spolski1, Steven E. Finkelstein2, SangKon Oh3, Panu E. Kovanen1, Christian S. Hinrichs2, Cynthia A. Pise-Masison4, Michael F. Radonovich4, John N. Brady4, Nicholas P. Restifo2, Jay A. Berzofsky3, and Warren J. Leonard1

1 Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute
2 Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
3 Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
4 Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

CORRESPONDENCE Warren J. Leonard: wjl{at}helix.nih.gov

Interleukin (IL)-21 is the most recently recognized of the cytokines that share the common cytokine receptor {gamma} chain ({gamma}c), which is mutated in humans with X-linked severe combined immunodeficiency. We now report that IL-21 synergistically acts with IL-15 to potently promote the proliferation of both memory (CD44high) and naive (CD44low) phenotype CD8+ T cells and augment interferon-{gamma} production in vitro. IL-21 also cooperated, albeit more weakly, with IL-7, but not with IL-2. Correspondingly, the expansion and cytotoxicity of CD8+ T cells were impaired in IL-21R–/– mice. Moreover, in vivo administration of IL-21 in combination with IL-15 boosted antigen-specific CD8+ T cell numbers and resulted in a cooperative effect on tumor regression, with apparent cures of large, established B16 melanomas. Thus, our studies reveal that IL-21 potently regulates CD8+ T cell expansion and effector function, primarily in a synergistic context with IL-15.

Abbreviations used: CFSE, 5,6-carboxyfluorescein diacetate succinimidyl ester; rFPVhgp100, recombinant fowlpox virus encoding hgp100; vPE16, vaccinia virus–expressing HIV gp160.


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