title: Dissociation of its opposing immunologic effects is critical for the optimization of antitumor CD8+ T-cell responses induced by interleukin 21.
abstract: OBJECTIVE
  Interleukin 21 (IL-21) is a promising new cytokine, which is undergoing clinical testing as an anticancer agent. Although IL-21 provides potent stimulation of CD8(+) T cells, it has also been suggested that IL-21 is immunosuppressive by counteracting the maturation of dendritic cells. The dissociation of these two opposing effects may enhance the utility of IL-21 as an immunotherapeutic. In this study, we used a cell-based artificial antigen-presenting cell (aAPC) lacking a functional IL-21 receptor (IL-21R) to investigate the immunostimulatory properties of IL-21.
  
  
  METHODS
  The immunosuppressive activity of IL-21 was studied using human IL-21R(+) dendritic cells. Antigen-specific CD8(+) T cells stimulated with human cell-based IL-21R(-)aAPC were used to isolate the T-cell immunostimulatory effects of IL-21. The functional outcomes, including phenotype, cytokine production, proliferation, and cytotoxicity were evaluated.
  
  
  RESULTS
  IL-21 limits the immune response by maintaining immunologically immature dendritic cells. However, stimulation of CD8(+) T cells with IL-21R(-) aAPC, which secrete IL-21, results in significant expansion. Although priming in the presence of IL-21 temporarily modulated the T-cell phenotype, chronic stimulation abrogated these differences. Importantly, exposure to IL-21 during restimulation promoted the enrichment and expansion of antigen-specific CD8(+) T cells that maintained IL-2 secretion and gained enhanced IFN-gamma secretion. Tumor antigen-specific CTL generated in the presence of IL-21 recognized tumor cells efficiently, demonstrating potent effector functions.
  
  
  CONCLUSIONS
  IL-21 induces opposing effects on antigen-presenting cells and CD8(+) T cells. Strategic application of IL-21 is required to induce optimal clinical effects and may enable the generation of large numbers of highly avid tumor-specific CTL for adoptive immunotherapy.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.forename: Marcus O
authors.initials: MO
authors.lastname: Butler
authors.forename: Alla
authors.initials: A
authors.lastname: Berezovskaya
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Murray
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevenson
authors.forename: Lee M
authors.initials: LM
authors.lastname: Nadler
authors.forename: Naoto
authors.initials: N
authors.lastname: Hirano
mesh_terms: D000938:Antigen-Presenting Cells / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007378:Interleukins / Q000378:metabolism*; D010641:Phenotype; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21