Cutting Edge: The Common γ-Chain Is an Indispensable Subunit of the IL-21 Receptor Complex

Asao, Hironobu; Okuyama, Chikara; Kumaki, Satoru; Ishii, Naoto; Tsuchiya, Shigeru; Foster, Donald M.; Sugamura, Kazuo

doi:10.4049/jimmunol.167.1.1

Cited by 487 publications

(423 citation statements)

References 30 publications

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“…A recent study shows that T-bet is required for IFN-␥ production in CD4 and NK cells, but not in CD8 T cells (40). T-bet can also stimulate indirectly its own gene expression by inducing IFN-␥, which in turn activates T-bet gene expression (41,42 (2,43). In addition, the IL-2/IL-15R␤ subunit that is essential for the proliferation of NK and T cells is also closely related to IL-21R.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Asao et al (2) suggested that IL-21 stimulation lead to the activation of JAK1 and JAK3 in a ␥ c -transfected T cell line. We analyzed whether JAK1 or JAK3 was activated by IL-21 also in NK and T cells.…”

Section: Il-21 Induces Jak1 and Jak3 Tyrosine Phosphorylationmentioning

confidence: 99%

“…IL-21R, expressed on both NK and T cells (1), is related to IL-2R␤ (3). It was recently shown that the common ␥-chain (␥ c ), 3 shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, is also the functional component of the IL-21R complex (2). Mice lacking the IL-2/IL-15R␤ chain do not have NK and T cells.…”

Section: Il-21 Up-regulates the Expression Of Genes Associated Withmentioning

confidence: 99%

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IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

Strengell

Sareneva

Foster

et al. 2002

The Journal of Immunology

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228

180

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IL-21 is a recently characterized T cell-derived cytokine that regulates NK and T cell function. IL-21R shares the common γ-chain (γc) with the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. Despite the same γc, these cytokines have different effects on diverse cells. In this study, we have studied IL-15- and IL-21-induced gene expression in human primary NK and T cells and the NK-92 cell line. Both IL-15 and IL-21 rapidly induced mRNA synthesis for IFN-γ, T-bet, IL-2Rα, IL-12Rβ2, IL-18R, and myeloid differentiation factor 88 (MyD88), the genes that are important in activating innate immunity and Th1 response. IL-15 induced STAT5 DNA binding to the IL-2Rα IFN-γ-activated sequence (GAS), MyD88 GAS, and c-sis-inducible elements, whereas IL-21 induced STAT3 DNA binding to MyD88 GAS and c-sis-inducible elements. IL-21-induced STAT3 activation was verified by immunoprecipitation and Western blotting with anti-phosphotyrosine Ab. In addition, pretreatment of NK-92 cells with IL-15 or IL-21 strongly enhanced IL-12-induced STAT4 DNA binding to IL-2Rα GAS. The induction of IFN-γ, T-bet, IL-12Rβ2, and IL-18R gene expression in NK cells, along with STAT3 activation, suggests that IL-21 is involved in the activation of innate immune responses. Moreover, the enhanced transcription of these genes in T cells establishes a significant role for IL-21 also in the Th1 response.

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Section: Discussionmentioning

confidence: 99%

Section: Il-21 Induces Jak1 and Jak3 Tyrosine Phosphorylationmentioning

confidence: 99%

Section: Il-21 Up-regulates the Expression Of Genes Associated Withmentioning

confidence: 99%

See 1 more Smart Citation

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

Strengell

Sareneva

Foster

et al. 2002

The Journal of Immunology

Self Cite

228

180

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“…The initial limitations of the SCID and NOD-SCID mice for the implantation and long term survival of human normal and neoplastic tissues have now been overcome by the generation of a new generation of NOD-SCID mouse with a null mutation of the IL-2 common γ chain receptor [130][131][132]. These NOD-SCID IL2Rγ null mice are called NOG mice, and the IL-2R mutation results in a defect of the high affinity receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 that blocks the development of NK cells and further impairs innate immunity [130,133].…”

Section: Mouse/human Xenograft Models To Study In Vivo Dynamic Interamentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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“…The IL-21 receptor complex consists of the common cytokine receptor g chain and IL-21R. 7,8 A recent study of mice lacking IL-21R demonstrated that IL-21 could facilitate the transition from NK cellmediated innate immunity to T cell-mediated adaptive immunity. 9 However, contradictory results were also reported; IL-21 is secreted from Th2 cells and inhibits the development of interferon-g (IFN-g)-producing Th1 cells.…”

mentioning

confidence: 99%

Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects

Ugai

Shimozato

et al. 2003

Cancer Gene Ther

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Keywords: IL-21; IL-23; pancreatic cancer; natural killer cells; gene therapy P ancreatic cancer is one of the intractable tumors and the prognosis remained unimproved despite recent progress in therapeutic and detection modalities. 1 It often infiltrates into neighboring tissues or vessels at an early stage and recurrence after surgical operation is common; therefore, a novel therapeutic strategy is required. Augmentation of a host immune system is an approach to suppress progression of the tumors and their metastasis, and transfer of cytokine genes into pancreatic cancer has been investigated for its clinical feasibility. 2,3 Cytokines released from T helper type 1 (Th1) cells are in particular effective in shifting immune systems into a Th1-dominant state, which enhances cell-mediated immunity. 4 Two novel cytokines, interleukin (IL)-21 and IL-23, were recently identified 5,6 and their biological properties analyzed in vitro were linked with Th1 functions. IL-21 is secreted primarily from CD4 + T cells and induces proliferation of activated T and natural killer (NK) cells. 5 IL-21 also increases the lytic functions of cytotoxic T and NK cells; 5 thereby, it can enhance antitumor immune responses. The IL-21 receptor complex consists of the common cytokine receptor g chain and IL-21R. 7,8 A recent study of mice lacking IL-21R demonstrated that IL-21 could facilitate the transition from NK cellmediated innate immunity to T cell-mediated adaptive immunity. 9 However, contradictory results were also reported; IL-21 is secreted from Th2 cells and inhibits the development of interferon-g (IFN-g)-producing Th1 cells. 10 IL-23 is composed of the p19 subunit, which is a novel molecule related to the p35 subunit of IL-12, and the p40

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Cutting Edge: The Common γ-Chain Is an Indispensable Subunit of the IL-21 Receptor Complex

Cited by 487 publications

References 30 publications

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

IL-21 Up-Regulates the Expression of Genes Associated with Innate Immunity and Th1 Response

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Transduction of the IL-21 and IL-23 genes in human pancreatic carcinoma cells produces natural killer cell-dependent and -independent antitumor effects

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