A Pivotal Role for Interleukin-27 in CD8<sup>+</sup>T Cell Functions and Generation of Cytotoxic T Lymphocytes

Morishima, Naohiko; Mizoguchi, Itaru; Okumura, Masae; Chiba, Yukino; Xu, Mingli; Shimizu, Motomu; Matsui, Masanao; Mizuguchi, Junichiro; Yoshimoto, Takayuki

doi:10.1155/2010/605483

Cited by 54 publications

(38 citation statements)

References 91 publications

(171 reference statements)

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“…In contrast to other forms of vaccination/immunization, T-cell intrinsic stimulation from classical Signal 3 cytokines such as type I IFN or IL-12 were not required for T-cell expansion, polarization, or memory generation (25,26). Literature searches for other cytokines capable of dramatically influencing T-cell polarization/differentiation drew attention to the IL-12 family member IL-27 (11,27,28). To investigate the potential role of IL-27 signaling in response to our subunit vaccination (TLR/CD40), IL-27RαKO and wild-type (WT) mice were immunized with antigen in the context of either Poly I:C/αCD40 or Pam3cys/αCD40, and the magnitude of the antigenspecific T-cell responses was monitored by tetramer staining at the peak of the response (day 7).…”

Section: Resultsmentioning

confidence: 99%

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Pennock

Gapin

Kedl

2014

Proc. Natl. Acad. Sci. U.S.A.

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An elusive goal of cellular immune vaccines is the generation of large numbers of antigen-specific T cells in response to subunit immunization. A broad spectrum of cytokines and cell-surface costimulatory molecules are known to shape the programming, magnitude, and repertoire of T cells responding to vaccination. We show here that the majority of innate immune receptor agonistbased vaccine adjuvants unexpectedly depend on IL-27 for eliciting CD4 + and CD8 + T-cell responses. This is in sharp contrast to infectious challenge, which generates T-cell responses that are IL-27-independent. Mixed bone marrow chimera experiments demonstrate that IL-27 dependency is T cell-intrinsic, requiring T-cell expression of IL-27Rα. Further, we show that IL-27 dependency not only dictates the magnitude of vaccine-elicited T-cell responses but also is critical for the programming and persistence of high-affinity T cells to subunit immunization. Collectively, our data highlight the unexpected central importance of IL-27 in the generation of robust, high-affinity cellular immune responses to subunit immunization.

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Section: Resultsmentioning

confidence: 99%

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Pennock

Gapin

Kedl

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-27 has been demonstrated to be a cytokine with potential effects on T cells, DCs and macrophages (3)(4)(5). As a member of the IL-12 family, IL-27 is another IFN-γ-inducing cytokine with substantial preclinical antitumor activity in several preclinical models that include both gene therapy and recombinant IL-27 (6-9).…”

Section: Discussionmentioning

confidence: 99%

“…Among 20 G418-resistant p28-IRES-EBI3 genetransduced cell colonies, we selected a colony (AsPC1/IL-27) that produced the largest amounts of IL-27 (167.64±8.37 pg/ml for 2x10 5 cells for 48 h). IL-27 in the supernatants of control (AsPC1/LXSN) cells was undetectable.…”

Section: Establishment Of Il-27-expressing Cellsmentioning

confidence: 99%

“…The biological functions of IL-12 and IL-27 are similar but not identical. IL-27 induces T-bet and IL-12R expression in naïve T cells, demonstrating that IL-27 plays a role in T cell maturation processes and generation of CTLs (5). The demonstration of significant antitumor activity in several preclinical animal tumor models has gained interest in the therapeutic use of IL-27 (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

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Effects on apoptosis and cell cycle arrest contribute to the antitumor responses of interleukin-27 mediated by retrovirus in human pancreatic carcinoma cells

et al. 2012

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Abstract. Interleukin (IL)-27, composed of p28 and EpsteinBarr virus-induced gene 3 (EBI3) subunits, has diverse functions in regulating immune systems. Human melanoma cells have been shown to express both IL-27 receptor subunits, and growth inhibition by IL-27 was detected. We investigated whether forced expression of the p28-linked EBI3 gene in human pancreatic carcinoma cells (AsPC1) by retroviral vector would produce IL-27-mediated antitumor effects and the related mechanisms. The data demonstrated that AsPC1 cells expressed both IL-27 receptor subunits, and tumor growth of AsPC1/IL-27 in mice was retarded compared with vector DNA-transduced tumors and survival of the mice was prolonged. Expression of cytokines such as interferon-γ, tumor necrosis factor-α and IL-1β in tumor specimens increased, while the secretion of IFN-γ and TNF-α from spleen cells of mice bearing IL-27-transfected tumors increased. Moreover, cell cycle arrest was induced in AsPC1/IL-27 inoculated mice with upregulated p21 expression and downregulated survivin expression. The appearance of apoptotic cells increased in tumor specimens of mice bearing IL-27-transfected tumors compared with the mice bearing DNA-transfected tumors by confirming the expression of apoptosis-related proteins and activated apoptotic pathways through detection of cleaved PARP. These results suggest that transfection of the IL-27 gene into human pancreatic carcinoma cells could produce antitumor effects in vivo and induction of cell cycle arrest and apoptosis could be the mechanism of IL-27 action in tumor regression.

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“…Finally, IL-27 which is a member of the IL-6/IL-12 heterodimeric cytokine family acts on naive CD4 + T cells and plays pivotal roles as a proinflammatory cytokine and generation of CTLs. Recent studies revealed that IL-27 plays an important role in CD8 + T cells as well [439].…”

Section: Chemokines and Cytokinesmentioning

confidence: 99%

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Schwendener¹,

Mete²

2013

Frontiers in Clinical Drug Research - Anti-Cancer Agents

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Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. lt;/pgt;lt;pgt; This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed. This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

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A Pivotal Role for Interleukin-27 in CD8⁺T Cell Functions and Generation of Cytotoxic T Lymphocytes

Cited by 54 publications

References 91 publications

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Effects on apoptosis and cell cycle arrest contribute to the antitumor responses of interleukin-27 mediated by retrovirus in human pancreatic carcinoma cells

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

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A Pivotal Role for Interleukin-27 in CD8+T Cell Functions and Generation of Cytotoxic T Lymphocytes

Cited by 54 publications

References 91 publications

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

IL-27 is required for shaping the magnitude, affinity distribution, and memory of T cells responding to subunit immunization

Effects on apoptosis and cell cycle arrest contribute to the antitumor responses of interleukin-27 mediated by retrovirus in human pancreatic carcinoma cells

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

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A Pivotal Role for Interleukin-27 in CD8⁺T Cell Functions and Generation of Cytotoxic T Lymphocytes