Bcl-2 Controls Dendritic Cell Longevity In Vivo

Nopora, Adam; Brocker, Thomas

doi:10.4049/jimmunol.169.6.3006

Cited by 110 publications

(115 citation statements)

References 45 publications

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“…Enhanced immunity by increased DC survival was reported in 'survival gene' Bcl-2 transgenic mice. 39 Coadministration of Bcl-xl and E7-based DNA vaccines via gene-gun generated enhanced E7-specific CD8+ T cell and memory response. 20,40,41 Our data show that augmented TRP2-specific-IFN-g-producing-CD8+ T-cell responses induced by mixed TRP2hsp70 DNA and CD11c-Bcl-xl DNA vaccine could last several weeks (Figure 3a).…”

Section: Discussionmentioning

confidence: 99%

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

et al. 2005

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T-cell priming is strongly affected by the longevity of antigenbearing dendritic cells (DCs), which are typically short-lived in lymphoid tissues. 'Survival gene' Bcl-xl is critical for the lifespan of DCs in vivo. Here, we showed that in vivo coadministration of Bcl-xl under control of the DC-specific promoter (CD11c-Bcl-xl) and TRP2hsp70 DNA prolonged T-cell stimulation by DCs and augmented TRP2-specific-IFNg-producing CD8+ T-cell responses. Consistent with these findings, enhanced protection and significant therapeutic immunity to B16 melanoma was generated by this coimmunization strategy, which also augmented therapeutic immunity to GL-26 tumor. In this B16 melanoma model, results from animal experiments with depletion of immune cells indicate that CD8+ T cells and NK cells are important in the antitumor immunity induced by this coimmunization strategy. These observations suggest that 'survival gene' Bcl-xl potentiates the magnitude of antigen-specific-CD8+ T-cell responses and the efficacy of antitumor immunity induced by DNA vaccine, and is relevant for the design of in vivo targeted DC-based vaccine strategies to improve immunity against cancer. Gene Therapy (2005) 12, 1517-1525.

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Section: Discussionmentioning

confidence: 99%

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

et al. 2005

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“…However, studies on the impact of Bcl-2 family gene transfection do not indicate whether intrinsic, extrinsic, or both apoptotic pathways are affected. DCs from CD11c-promoter-driven bcl-2 transgenic mice display increased longevity in vitro and in vivo and induce augmented immune responses when transferred into WT recipients (21). Activated T cells secrete TNF-related activation-induced cytokine (TRANCE) and express CD40L, molecules that have been shown to improve survival of cultured bone-derived or splenic DCs, and correlate with an increase in Bcl-x L and Bcl-2 expression, respectively (37,38).…”

Section: Discussionmentioning

confidence: 99%

CD4 T Cell-Induced, Bid-Dependent Apoptosis of Cutaneous Dendritic Cells Regulates T Cell Expansion and Immune Responses

Pradhan¹,

Genebriera²,

Denning

et al. 2006

The Journal of Immunology

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The fate of dendritic cells (DCs) after Ag presentation may be DC subset-specific and controlled by many factors. The role of activation-induced apoptosis in regulating DC function is not clear. We investigated the fate of cutaneous DCs (cDCs), specifically Langerhans cells (LCs), and observed that they undergo apoptosis after successful Ag presentation to CD4 T cells. Caspase-specific inhibitors revealed that LC lines use a type II apoptosis pathway in response to CD4 T cells. In support of this, BH3-interacting domain (Bid) protein was present at high levels and specifically cleaved in the presence of Ag-specific T cells. Significant resistance to apoptosis by OT-2 CD4 cells was also observed for Bid knockout (KO) LCs in vitro. To test whether Bid was required to regulate LC function in vivo, we measured contact sensitization and topical immunization responses in Bid KO mice and observed markedly enhanced ear swelling and proliferation responses compared with wild-type mice. Furthermore, when Ag-pulsed Bid KO migratory cDCs were inoculated into wild-type recipients, an increase in both the rate and percentage of expanded OT-2 T cells expressing IFN-γ was observed. Thus, enhanced Ag presentation function was intrinsic to Bid KO cDCs. Therefore, Bid is an important regulator of LC viability and Ag presentation function.

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“…7,8 Although all the factors that regulate DC lifespan are not yet known, ligands for Toll-like receptors and T cell-expressed costimulatory molecules (for example, CpG, CD40L and TRANCE) prolong the survival of DCs through the expression of antiapoptotic factors, such as Bcl-2 and Bcl-x L . [9][10][11][12][13][14] Furthermore, Bcl-x Ldeficient DCs, which are isolated from Bcl-x L fl/fl mice, fail to induce effective immune responses in vivo, which correlates with their rapid disappearance from the draining LNs due to apoptosis. 13 These findings led us to speculate that DC-based vaccination could be enhanced by engineering DCs to overexpress antiapoptotic protein using gene-transfer methods to inhibit apoptosis and prolong the survival of antigen-presenting DCs in vivo.…”

Section: Introductionmentioning

confidence: 99%

Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency

et al. 2008

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Dendritic cells (DCs) have a critical role in the induction of antigen-specific immune responses, transporting antigens from peripheral tissue to regional lymph nodes where they interact with antigen-specific T lymphocytes. Recent studies revealed that the efficacy of the T cell-dependent immune response depends on the lifespan of the antigen-presenting DCs in the lymph nodes. Here, we succeeded in engineering long-lived antigen-presenting DCs via Bcl-x L -derived hyperactive mutant antiapoptotic protein (Bcl-x FNK ) gene transfer. In a B16BL6 melanoma model, these long-lived DCs exerted potent antitumor immunity that depended mainly on antigenspecific cytotoxic T lymphocytes. Furthermore, in vivo longevity of the long-lived DC vaccine led to antigen-specific activation of interferon-g-producing CD4 + and CD8 + T cells. Thus, the long-lived DC vaccine strategy is highly useful for constructing DC vaccines, as well as other cell-based medicines, such as stem cell therapy.

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Bcl-2 Controls Dendritic Cell Longevity In Vivo

Cited by 110 publications

References 45 publications

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

CD4 T Cell-Induced, Bid-Dependent Apoptosis of Cutaneous Dendritic Cells Regulates T Cell Expansion and Immune Responses

Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency

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