title: Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function.
abstract: 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.
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Steven E
authors.initials: SE
authors.lastname: Finkelstein
authors.forename: SangKon
authors.initials: S
authors.lastname: Oh
authors.forename: Panu E
authors.initials: PE
authors.lastname: Kovanen
authors.forename: Christian S
authors.initials: CS
authors.lastname: Hinrichs
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Pise-Masison
authors.forename: Michael F
authors.initials: MF
authors.lastname: Radonovich
authors.forename: John N
authors.initials: JN
authors.lastname: Brady
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D004357:Drug Synergism; D005434:Flow Cytometry; D005452:Fluoresceins; D019302:HIV Envelope Protein gp160; D007156:Immunologic Memory / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015851:Interleukin-7 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D013388:Succinimides; D000098546:Interleukin-21
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D019302:HIV Envelope Protein gp160; D019409:Interleukin-15; D015851:Interleukin-7; D007378:Interleukins; D013388:Succinimides; D007371:Interferon-gamma; D000098546:Interleukin-21