IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-γ Production in Human NK and T Cells

Strengell, Mari; Matikainen, Sampsa; Sirén, Jukka; Lehtonen, Ari; Foster, Donald M.; Julkunen, Ilkka; Sareneva, Timo

doi:10.4049/jimmunol.170.11.5464

Cited by 353 publications

(320 citation statements)

References 41 publications

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“…This suggests that a STAT4-independent pathway is sufficient to support naive CD8 T cell acquisition of cytolytic activity and that among the known third-signal cytokines, this pathway is exclusive to IL-21. It is unlikely that this alternate pathway is STAT1 mediated, because all-third signal cytokines activate STAT1 (19,29,40,41), but none requires it for the induction of cytolytic activity (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…Of the three known third-signal cytokines, IL-21 is the only one belonging to the ␥ c cytokine family. Although all of the thirdsignal cytokines activate STAT4 (19,34,39), IL-21 is uniquely capable of inducing cytolytic activity in the absence of STAT4 (Fig. 4).…”

Section: Discussionmentioning

confidence: 99%

“…2a); however, synergistic interactions have been reported for IL-21 and other IL-2 family members (19,23). Although we do not add exogenous IL-2 to the cultures, CD8 T cells are capable of transient autocrine IL-2 production upon activation (10,27,28).…”

Section: Optimal Il-21 Induction Of Cd8 T Cell Cytolytic Activity Reqmentioning

confidence: 99%

“…Initially, IL-21 was reported to induce proliferation of bulk T cells upon stimulation with anti-CD3 mAb by enhancing the effects of IL-2, IL-15, and, to a lesser extent, IL-7 (17). IL-21 has also been shown to act in synergy with IL-18 and IL-15 in the induction of IFN-␥ production by human bulk T and NK cells (19). In addition, administration of IL-21 in three separate tumor models proved to have protective and/or therapeutic benefits (20 -22).…”

Section: Il-21 Promotes Differentiation Of Naive Cd8 T Cells To a Unimentioning

confidence: 99%

“…IL-21 is also a strong inducer of STAT1 activation (19,29), and mice deficient in STAT1 have demonstrated defective tumor rejection, suggesting a failure to develop an effective CD8 T cell response (30). A direct role for STAT1 in the up-regulation of cytolytic effector function is also suggested by the IL-6-induced binding of STAT1a to a functional STAT-binding element in the human perforin promoter (31,32).…”

Section: Il-21 Signaling Requirements For the Initiation Of Differentmentioning

confidence: 99%

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IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

The Journal of Immunology

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IL-21, the most recently described member of the common γ-chain cytokine family, is produced by activated CD4 T cells, whereas CD8 T cells express the IL-21 receptor. To investigate a possible role for IL-21 in the priming of naive CD8 T cells, we examined responses of highly purified naive OT-I CD8 T cells to artificial APCs displaying Ag and B7-1 on their surface. We found that IL-21 enhanced OT-I clonal expansion and supported development of cytotoxic effector function. High levels of IL-2 did not support development of effector functions, but IL-2 was required for optimal responses in the presence of IL-21. IL-12 and IFN-α have previously been shown to support naive CD8 T cell differentiation and acquisition of effector functions through a STAT4-dependent mechanism. Here, we show that IL-21 does not require STAT4 to stimulate development of cytolytic activity. Furthermore, IL-21 fails to induce IFN-γ or IL-4 production and can partially block IL-12 induction of IFN-γ production. CD8 T cells that differentiate in response to IL-21 have a distinct surface marker expression pattern and are characterized as CD44high, PD-1low, CD25low, CD134low, and CD137low. Thus, IL-21 can provide a signal required by naive CD8 T cells to differentiate in response to Ag and costimulation, and the resulting effector cells represent a unique effector phenotype with highly effective cytolytic activity, but deficient capacity to secrete IFN-γ.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Optimal Il-21 Induction Of Cd8 T Cell Cytolytic Activity Reqmentioning

confidence: 99%

Section: Il-21 Promotes Differentiation Of Naive Cd8 T Cells To a Unimentioning

confidence: 99%

Section: Il-21 Signaling Requirements For the Initiation Of Differentmentioning

confidence: 99%

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IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

The Journal of Immunology

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Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

Shao,

Bai,

Zhu

et al. 2023

Adv Healthcare Materials

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Natural killer (NK) cells have emerged as an important contributor to cancer immunotherapy, but their antitumor efficacy remains suboptimal. While cytokine‐based priming shows promise in enhancing NK‐cell activity, its clinical translation faces many challenges, including co‐activation of multiple cytokines, poor pharmacokinetics, and limited mechanistic understanding. Here, we developed a polymeric micelle‐based IL‐15/IL‐2 codelivery system (IL‐15/2‐PEG‐PTMC) for NK‐cell activation. In vivo studies demonstrated that the half‐life of IL‐15 and IL‐2 as well as the recruitment of NK cell within tumor tissue was significantly increased after PEG‐PTMC loading. Coupled with the coactivation effect of IL‐15 and IL‐2 conferred by this polymeric micelle‐based system, it noticeably delayed the growth of tumors in mice compared to conventional NK cell activation approach, that was free IL‐15 and IL‐2. We also surprisingly found that cholesterol metabolism was highly involved in the NK cell activation by IL‐15/2‐PEG‐PTMC. Following stimulation with IL‐15/2‐PEG‐PTMC or IL‐15, NK cells underwent a series of cholesterol metabolism reprogramming, which elevated the cholesterol levels on the NK cell membrane. This in turn promoted the formation of lipid rafts and actived immune synapse, effectively contributing to the enhancement of the NK cell's anti‐tumor activity. We believe this will open a new avenue for improving the efficacy of NK cell immunotherapy by regulating cholesterol metabolism.This article is protected by copyright. All rights reserved

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Interleukin‐21 Receptor Blockade Inhibits Secondary Humoral Responses and Halts the Progression of Preestablished Disease in the (NZB × NZW)F1 Systemic Lupus Erythematosus Model

Zhang

Chan

et al. 2015

Arthritis & Rheumatology

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Objective. Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin-21 (IL-21) or IL-21 receptor (IL-21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL-21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL-21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB 3 NZW)F1 (NZB/NZW) mouse model of SLE.Methods. Humoral and cellular immune responses to immunization with sheep red blood cells (SRBCs) were measured in mice dosed with IL-21R blocking antibodies. Progression of nephritis and markers of immune activation was monitored in NZB/NZW mice following different anti-IL-21R treatment regimens.Results. IL-21R blockade specifically inhibited secondary IgG responses to SRBC immunization. In NZB/NZW mice, IL-21R blockade completely inhibited the onset of nephritis, which was associated with dramatic reductions in splenomegaly and in B cell and T cell activation. When administered to mice with preexisting disease, anti-IL-21R antibody halted the disease progression and mortality and reversed the nephritis in a subset of mice. Furthermore, treatment cessation was not followed by rapid reemergence of disease. Conclusion. Our results highlight the importance of IL-21 in promoting humoral recall responses and in sustaining autoimmune inflammation.Interleukin-21 (IL-21), a member of the type I/ common g-chain family of cytokines, is in many respects, the quintessential "helper" cytokine, in that it is expressed primarily by CD41 T cells and induces effector mechanisms in all lymphocytes (1). Although dispensable for normal B and T cell development, IL-21 is required for T celldependent affinity-matured antibody production in response to immunization, and it drives autoantibody production in rodent models of lupus, type 1 diabetes mellitus, and arthritis (1). A key driver of germinal center formation, IL-21 acts on both B cells and, in an autocrine manner, follicular helper T (Tfh) cells to sustain B cell maturation, antibody class switching, and ultimately, plasma cell formation (2). Similarly, in in vitro assays for human T cell-dependent B cell activation, IgG and IgA production is entirely IL-21 dependent (3). IL-21 also stimulates CD41 and CD81 T cell differentiation and production of multiple proinflammatory mediators, such as IL-17, interferon-g (IFNg), chemokines, granzymes, and perforin (1).In mouse models of spontaneous autoimmunity, such as systemic lupus erythematosus (SLE), type 1 diabetes mellitus, and arthritis, IL-21/IL-21 receptor (IL-21R) deficiency completely abrogates all manifestations of disease (1,4). Furthermore, in a model of chronic viral infection characterized by attenuated CD81 T c...

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IL-21 in Synergy with IL-15 or IL-18 Enhances IFN-γ Production in Human NK and T Cells

Cited by 353 publications

References 41 publications

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Construction and Mechanism of IL‐15‐Based Coactivated Polymeric Micelles for NK Cell Immunotherapy

Interleukin‐21 Receptor Blockade Inhibits Secondary Humoral Responses and Halts the Progression of Preestablished Disease in the (NZB × NZW)F1 Systemic Lupus Erythematosus Model

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