Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

Stonier, Spencer W.; Lisa, James R.; Castillo, Eliseo F.; Schluns, Kimberly S.

doi:10.1182/blood-2008-05-156307

Cited by 100 publications

(130 citation statements)

References 36 publications

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“…These data might seem to contrast previous data showing that restricting expression of IL-15Ra to CD11c þ DCs resulted in a partial rescue of KLRG1 hi CD127 lo CD8 þ T cells. 31 However, only partial effects were observed in the prior study and we failed to observe enhancement of DCs in Bim-deficient mice during viral infection, suggesting that other cell types are important presenters of IL-15. Thus, Bim expression within DCs has little, if any, role on the magnitude or phenotype of the effector CD8 þ T-cell response to acute viral infection.…”

Section: Discussioncontrasting

confidence: 56%

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Kurtuluş

Sholl

et al. 2014

Cell Death Differ

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During the effector CD8 þ T-cell response, transcriptional differentiation programs are engaged that promote effector T cells with varying memory potential. Although these differentiation programs have been used to explain which cells die as effectors and which cells survive and become memory cells, it is unclear if the lack of cell death enhances memory. Here, we investigated effector CD8 þ T-cell fate in mice whose death program has been largely disabled because of the loss of Bim. Interestingly, the absence of Bim resulted in a significant enhancement of effector CD8 þ T cells with more memory potential. Bim-driven control of memory T-cell development required T-cell-specific, but not dendritic cell-specific, expression of Bim. Both total and T-cell-specific loss of Bim promoted skewing toward memory precursors, by enhancing the survival of memory precursors, and limiting the availability of IL-15. Decreased IL-15 availability in Bim-deficient mice facilitated the elimination of cells with less memory potential via the additional pro-apoptotic molecules Noxa and Puma. Combined, these data show that Bim controls memory development by limiting the survival of pre-memory effector cells. Further, by preventing the consumption of IL-15, Bim limits the role of Noxa and Puma in causing the death of effector cells with less memory potential.

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Section: Discussioncontrasting

confidence: 56%

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Kurtuluş

Sholl

et al. 2014

Cell Death Differ

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“…Many studies have demonstrated that anti-tumor immunity and the ability to break tolerance could be enhanced by co-delivering additional immunomodulator genes, such as interleukin-2, interleukin-12, interleukin-15, CD70 and other activators, to DCs. 5,[57][58][59][60] We are currently conducting experiments to evaluate the anti-tumor immunity generated by the co-delivery of a tumor antigen and an immuomodulator using this DC-directed lentivector system.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

Yang

Liang

et al. 2011

Cancer Gene Ther

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Lentivectors are potential vaccine delivery vehicles because they can efficiently transduce a variety of non-dividing cells, including antigen-presenting cells, and do not cause expression of extra viral proteins. To improve safety while retaining efficiency, a dendritic cell (DC)-specific lentivector was constructed by pseudotyping the vector with an engineered viral glycoprotein derived from Sindbis virus. We assessed the level of anti-tumor immunity conferred by this engineered lentivector encoding the melanoma antigen gp100 in a mouse model. Footpad injection of the engineered lentivectors results in the best antigen-specific immune response as compared with subcutaneous and intraperitoneal injections. A single prime vaccination of the engineered lentivectors can elicit a high frequency (up to 10%) of gp100-specific CD8 þ T cells in peripheral blood 3 weeks after the vaccination and this response will be maintained at around 5% for up to 8 weeks. We found that these engineered lentivectors elicited relatively low levels of anti-vector neutralizing antibody responses. Importantly, direct injection of this engineered lentivector inhibited the growth of aggressive B16 murine melanoma. These data suggest that DC-specific lentivectors can be a novel and alternative vaccine carrier with the potential to deliver effective anti-tumor immunity for cancer immunotherapy.

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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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Dendritic cells drive memory CD8 T-cell homeostasis via IL-15 transpresentation

Cited by 100 publications

References 36 publications

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

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

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