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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5326-5333.
Prepublished online as a Blood First Edition Paper on February 15, 2008; DOI 10.1182/blood-2007-09-113050.


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IMMUNOBIOLOGY

IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy

Christian S. Hinrichs*,1, Rosanne Spolski*,2, Chrystal M. Paulos1, Luca Gattinoni1, Keith W. Kerstann1, Douglas C. Palmer1, Christopher A. Klebanoff1, Steven A. Rosenberg1, Warren J. Leonard{dagger},2, and Nicholas P. Restifo{dagger},1

1 National Cancer Institute (NCI), Surgery Branch, National Institutes of Health (NIH), Bethesda, MD; and 2 National Heart, Lung and Blood Institute (NHLBI), Laboratory of Molecular Immunology, NIH, Bethesda, MD

IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naive CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of Eomesodermin (Eomes) and maturation of naive CD8+ T cells into granzyme B- and CD44-expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2–mediated acquisition of a cytolytic CD8+ T-cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2 impaired the subsequent antitumor function of transferred cells. Gene expression studies revealed a distinct IL-21 program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced antitumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies.


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