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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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-09-113050v1 blood-2007-09-113050v2 111/11/5326    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hinrichs, C. S. Articles by Restifo, N. P. Search for Related Content PubMed PubMed Citation Articles by Hinrichs, C. S. Articles by Restifo, N. P. Related Collections Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  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,2, and Nicholas P. Restifo,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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: IL-21 priming enhances T-cell immunotherapy Phillip K. Darcy Blood 2008 111: 5268-5269. [Full Text] [PDF] This article has been cited by other articles: C. S. Hinrichs, Z. A. Borman, L. Cassard, L. Gattinoni, R. Spolski, Z. Yu, L. Sanchez-Perez, P. Muranski, S. J. Kern, C. Logun, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity PNAS, October 13, 2009; 106(41): 17469 - 17474. [Abstract] [Full Text] [PDF] C. A. Klebanoff, Z. Yu, L. N. Hwang, D. C. Palmer, L. Gattinoni, and N. P. Restifo Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination Blood, August 27, 2009; 114(9): 1776 - 1783. [Abstract] [Full Text] [PDF] C. S. Hinrichs, A. Kaiser, C. M. Paulos, L. Cassard, L. Sanchez-Perez, B. Heemskerk, C. Wrzesinski, Z. A. Borman, P. Muranski, and N. P. Restifo Type 17 CD8+ T cells display enhanced antitumor immunity Blood, July 16, 2009; 114(3): 596 - 599. [Abstract] [Full Text] [PDF] L. D. S. Johnson and S. C. Jameson A Chronic Need for IL-21 Science, June 19, 2009; 324(5934): 1525 - 1526. [Abstract] [Full Text] [PDF] D. A. Hagge, B. M. Saunders, G. J. Ebenezer, N. A. Ray, V. T. Marks, W. J. Britton, J. L. Krahenbuhl, and L. B. Adams Lymphotoxin-{alpha} and TNF Have Essential but Independent Roles in the Evolution of the Granulomatous Response in Experimental Leprosy Am. J. Pathol., April 1, 2009; 174(4): 1379 - 1389. [Abstract] [Full Text] [PDF] A. Thedrez, C. Harly, A. Morice, S. Salot, M. Bonneville, and E. Scotet IL-21-Mediated Potentiation of Antitumor Cytolytic and Proinflammatory Responses of Human V{gamma}9V{delta}2 T Cells for Adoptive Immunotherapy J. Immunol., March 15, 2009; 182(6): 3423 - 3431. [Abstract] [Full Text] [PDF]

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