IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Kokaji, Andy I.; Hockley, Deanna L.; Kane, Kevin P.

doi:10.4049/jimmunol.180.7.4391

Cited by 44 publications

(45 citation statements)

References 59 publications

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“…Interleukin 15 (IL-15) is a pivotal cytokine for the activation and proliferation of cytotoxic CD8 + T cells (1)(2)(3). As opposed to other soluble cytokines that induce signals upon binding to their respective receptors, IL-15 delivery is relatively unique (4).…”

Section: Cytotoxic Cd8mentioning

confidence: 99%

IL-15, in synergy with RAE-1ɛ, stimulates TCR-independent proliferation and activation of CD8+ T cells

Zhang

Pan

et al. 2011

Oncology Letters

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Abstract. CD8+ T cells play critical roles in immunosurveil lance by killing malignant or virally infected cells. Interleukin 15 (IL-15) is a critical cytokine for promoting proliferation and the effector capacity of CD8 + T cells, and has been used to support the growth of CD8 + T cells in cellular therapies of neoplastic diseases. Recent studies have shown that IL-15, in synergy with other cytokines, such as IL-6, enhances the T-cell receptor (TCR)-independent proliferation and function of CD8 + T cells. The aim of the present study was to investigate the role of BaF3-mb15-RAE cells in stimulating mouse CD8 + T cells. BaF3 cells were cultured and B16F10 cells were grown in DMEM. MTT assay was used to detect the proliferation of CD8 + T cells. Cells were analyzed using flow cytometry. The results showed that IL-15 synergistically acts with another T-cell stimulatory molecule, RAE1ε, to potently promote the proliferation of CD8 + T cells, induce CD8 + T-cell activation and enhance granzyme B and interferon-γ (IFN-γ) production in the absence of signaling via the TCR. Moreover, IL-15 in combination with RAE1ε resulted in a cooperative effect on CD8 + T-cell-mediated cytotoxicity against B16F10 tumor cells. Thus, results of the present study showed that IL-15, in synergy with RAE1ε, enhances the TCR-independent effector function of CD8 + T cells in vitro, which may be useful in the cellular immunotherapy of cancer. Introduction Cytotoxic CD8+ T cells are effector cells that play a key role in immunosurveillance through the elimination of malignant or virally infected cells. Interleukin 15 (IL-15) is a pivotal cytokine for the activation and proliferation of cytotoxic CD8 + T cells (1-3). As opposed to other soluble cytokines that induce signals upon binding to their respective receptors, IL-15 delivery is relatively unique (4). IL-15 bound to its high-affinity receptor (IL-15R)α-chain may be retained on the cell surface and presented in trans to target cells such as CD8 + T cells, which express only IL-2/15Rβ and γ (5). The receptor-cytokine complex may act as a membrane-bound stimulatory molecule in a contact-dependent manner (6). Numerous studies raised the possibility that the IL-15/IL-15Rα complex is a promising and potent agent for tumor immunotherapy (7-11).NKG2D is an activating receptor present on the surface of mouse and human NK, γδT, human CD8 + T and activated mouse CD8 + T cells (12,13). The ligands for the NKG2D receptor include RAE1 (RAE1α-RAE1ε), Mult1 and H60 in the mouse, and MICA/B and RAET1, also known as UL-16 binding proteins (ULBPs), in the human (14,15). Results of previous studies showed that NKG2D may function as a costimulatory receptor for both mouse and human CD8 + T cells (16,17). IL-15 selectively upregulates the expression and function of NKG2D (18). In addition, IL-15 confers NK-like activity to effector CD8 + T cells, unveiling the cytotoxic properties of NKG2D (18).Since NKG2D and IL-15 play significant roles in the activation and/or expansion of CD8 + T cells (as mentioned above...

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Section: Cytotoxic Cd8mentioning

confidence: 99%

IL-15, in synergy with RAE-1ɛ, stimulates TCR-independent proliferation and activation of CD8+ T cells

Zhang

Pan

et al. 2011

Oncology Letters

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“…The cytokine-induced killer cells (CIK cells) are also expressing receptors such as NKG2D, which are responsible for cytotoxicity, triggering of granule exocytosis and feedback cytokine toxicity secretion. IL-15 is responsible for the survival, proliferation and synthesis of IFN-γ (through feedback), perforin and granzyme B in natural killer cells and CD8+ [37,[40][41][42][43]. The mode of action of IL-15 is through a ``trans-presentation``, where IL-15Rα (surface of macrophages, dendritic cells and epithelial cells) presents IL-15 in trans to responder cells (CD8+ and NK) which have IL-15Rβ/γ [44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Interleukin-8 and Interleukin-17 for Cancer

Zarogoulidis¹,

Katsikogianni²,

Tsiouda³

et al. 2014

Cancer Investigation

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Interleukin 7 and 15 are considered powerful pro-inflammatory cytokines, they have the ability to destabilize chromosomes and induce tumorigenesis. Additionally, they can control malignancy proliferation by influencing the tumor microenvironment and immune system. Immunotherapy has been proposed as a treatment modality for malignancy for over a decade; the exact mechanisms of action and pathways are still under investigation. Interleukin 7 and 15 have been extensively investigated in hematological malignancies since their mode of action influences the stimulation of the immune system in a more direct way than other malignancies such as lung, melanoma, and breast, renal and colorectal cancer.

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“…9 To improve on the oncolytic efficacy of VSV, we have added a highly secreted form of human IL-15 to our oncolytic VSV vector for its immuno-stimulatory effects on innate and acquired immunity. 12,15,16,35 The addition of the hIL-15 transgene did not impair viral replication in vitro and led to high levels of secretion of hIL-15 from virally infected cells both in vitro and in vivo. We predicted that expression of IL-15 from our virus would enhance therapy, as it has been shown previously that IL-15 expressed from transfected tumors We failed to see an enhancement to therapy when we first tested our viruses in the subcutaneous version of the CT26 model as the parental GFP-expressing virus was already very efficacious in this setting.…”

Section: Discussionmentioning

confidence: 99%

“…IL-15 is a member of the 4-a helix family of cytokines and signals through a receptor complex that includes both the IL-15-specific receptor a chain (IL-15/Ra) and the b g common chain. 12 IL-15 has been shown to play important roles in numerous immunological processes, including natural killer (NK) cell proliferation and activation, 13,14 CD8 T-cell activation, in particular, memory cell development 15 and is able to rescue tolerized T cells ex vivo. 16 As well, the treatment of established tumors with IL-15 improves survival 17 and pre-association of IL-15 to its receptor a chain further enhances NK and CD8 T-cell activation, proliferation 18,19 and anti-tumour activity.…”

Section: Introductionmentioning

confidence: 99%

Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity

et al. 2011

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In this study, we sought to enhance the potency of an oncolytic virus, vesicular stomatitis virus (VSV), by inserting a transgene encoding a highly secreted version of human interleukin-15 (IL-15). IL-15 has shown promise as an immunotherapeutic cytokine, as it is able to enhance both natural killer (NK) and T-cell responses, but it has not yet been tested as a therapeutic transgene in the context of viral oncolysis. The transgene was modified to ensure enhanced secretion of IL-15 from infected cells, leading to strong localized expression from infected CT-26 tumors in vivo. This localized expression in the tumor microenvironment led to a clear enhancement to anti-tumoral T-cell responses and enhanced survival, while additional IL-15 administration systemically failed to further enhance the therapy. Overall, the transient localized expression of IL-15 in the tumour by an oncolytic virus was able to induce stronger anti-tumoral immunity in a murine model of colon carcinoma.

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IL-15 Transpresentation Augments CD8+ T Cell Activation and Is Required for Optimal Recall Responses by Central Memory CD8+ T Cells

Cited by 44 publications

References 59 publications

IL-15, in synergy with RAE-1ɛ, stimulates TCR-independent proliferation and activation of CD8+ T cells

IL-15, in synergy with RAE-1ɛ, stimulates TCR-independent proliferation and activation of CD8+ T cells

Interleukin-8 and Interleukin-17 for Cancer

Expressing human interleukin-15 from oncolytic vesicular stomatitis virus improves survival in a murine metastatic colon adenocarcinoma model through the enhancement of anti-tumor immunity

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