Induction of antigen-specific immunosuppression by CD95L cDNA-transfected 'killer' dendritic cells

Matsue, Hiroyuki; Matsue, Keiko; Walters, Michael A.; Okumura, Ko; Yagita, Hideo; Takashima, Akira

doi:10.1038/11375

Cited by 150 publications

(158 citation statements)

References 46 publications

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“…In murine systems antigen-specific T cell deletion and tolerance induction in vitro and in vivo was achieved by CD95L-transfected APC. 14,15 Also in the human system mature but not immature human DC retrovirally transduced with murine CD95L induced apoptosis induction in CD95-expressing T cells in vitro. 25 However, to our knowledge, efficient alloantigen-specific depletion by APC expressing m-CD95L without impairment of immunity towards environmental antigens is shown here for the first time in the human system.…”

Section: Cd95l Expressed On T Cells Mediates a Dual Functionmentioning

confidence: 98%

“…13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models. 14,15 This approach benefits from the high specificity since only T cells responding to the antigen expressed on the APC are deleted by CD95/CD95L interaction while the remaining T cells are still responsive to unrelated antigens. However, successful elimination of antigen-specific T cells via the CD95 system depends on the CD95-sensitivity of T cells.…”

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confidence: 99%

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Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

et al. 2006

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Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4 þ and CD8 þ HLA-A1-specifc T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases. Apoptosis mediated by the CD95 system plays a pivotal regulatory role in the maintenance of immune homeostasis. Deficiency in CD95 or CD95L expression in T cells mediates lymphoproliferative disorders due to the lack of apoptosis induction. 1 Paradoxically, several molecules of the CD95 signaling pathway are also required for T cell activation and proliferation. 2 In addition to T cells, live and death of antigenpresenting cells, which initiate T cell responses has to be tightly controlled to avoid the establishment of autoimmunity. 3 Activation-induced cell death (AICD) represents an apoptosis mechanism mediated via the interaction of CD95 with its ligand CD95L, to mediate T cell death and initiate the termination of an immune response to maintain tolerance to self antigens and to prevent autoimmunity. 4 Owing to the constitutive expression of CD95L in immune privileged organs such as testis or eye, 5,6 CD95L was considered as an immunoprotective agent able to counterattack activated T cells in vivo. However, the role of CD95L in transplantation tolerance is still controversial. While allogeneic pancreatic islands transplanted together with syngeneic CD95L expressing myoblasts were tolerated, 7 allogeneic CD95L expressing pancreatic b cells were rejected due to increased neutrophil infiltration. 8 Lack of immunogenicity of tumors and resistance towards T cell attacks were also correlated with the expression of CD95L on tumor tissues. Such tumors were shown to kill CD95-positive cells in vitro. 9 However, transfection of CD95L into murine tumor cells did not enhance tumor growth, but instead induced accelerated tumor rejection by neutrophils in vivo. [10][11][12] Systemic immunomodulation by CD95L was successfully achieved by antigen-presenting cells modified to express CD95L. 13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models. 14,15 This approach benefits from the hig...

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Section: Cd95l Expressed On T Cells Mediates a Dual Functionmentioning

confidence: 98%

mentioning

confidence: 99%

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

et al. 2006

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“…However, all these studies were performed using murine DC, B cells, macrophages, or cell lines as APC (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)39). Therefore, for future clinical application, it had to be determined whether human DC can be efficiently transduced with FasL and whether these cells would be capable of eliminating Fas ϩ target cells.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, experiments to generate FasL-expressing APC from primary human cells are still lacking. Because several studies demonstrated that FasL is highly conserved within different species and that murine FasL induces apoptosis in human Fas ϩ cells (18), we investigated in the present study whether primary human monocytederived immature DC (iDC) and mature DC (mDC) could be transduced with murine FasL using an inducible Cre/Loxp adenovirusbased gene transfer system to generate killer APC.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC

Hoves

Krause²,

Halbritter³

et al. 2003

The Journal of Immunology

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Several in vitro and animal studies have been performed to modulate the interaction of APCs and T cells by Fas (CD95/Apo-1) signaling to delete activated T cells in an Ag-specific manner. However, due to the difficulties in vector generation and low transduction frequencies, similar studies with primary human APC are still lacking. To evaluate whether Fas ligand (FasL/CD95L) expressing killer APC could be generated from primary human APC, monocyte-derived dendritic cells (DC) were transduced using the inducible Cre/Loxp adenovirus vector system. Combined transduction of DC by AdLoxpFasL and AxCANCre, but not single transduction with these vectors, resulted in dose- and time-dependent expression of FasL in >70% of mature DC (mDC), whereas <20% of immature DC (iDC) expressed FasL. In addition, transduction by AdLoxpFasL and AxCANCre induced apoptosis in >80% of iDC, whereas FasL-expressing mDC were protected from FasL/Fas (CD95/Apo-1)-mediated apoptosis despite coexpression of Fas. FasL-expressing mDC eliminated Fas+ Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted. Induction of apoptosis in Fas+ target cells required expression of FasL in DC and cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. Induction of apoptosis in Fas+ target cells required expression of FasL in DC, cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. The present results demonstrate that FasL-expressing killer APC can be generated from human monocyte-derived mDC using adenoviral gene transfer. Our results support the strategy to use killer APCs as immunomodulatory cells for the treatment of autoimmune disease and allograft rejection.

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“…Both the XS106 LC line and NF46 fibroblasts were established from the epidermis of newborn A/J mice and maintained in vitro, as described previously (12)(13)(14).…”

Section: Animals and Cell Linesmentioning

confidence: 99%

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

Timares

Safer

et al. 2003

The Journal of Immunology

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Determining the mechanism of Ag loading of Langerhans cells (LC) for genetic immunization (GI) is complicated by the inability to distinguish between the response generated by direct transfection of LC from that due to exogenous uptake. To unravel this mechanism, we examined the impact of gene gun treatment on LC with respect to their activation and migration from skin, transgene expression, and ability to initiate humoral and cellular immune responses upon transfer to naive mice. To assess responses generated by direct LC transfection, an RU486-inducible expression system was used as a GI vector. In vitro skin organ cultures were developed from gene gun immunized mouse ear specimens to obtain LC. Gene gun treatment markedly augmented (3-fold) LC migration from ear skin, and these LC expressed the transgene at RNA and protein levels. Transfer of 2 × 105 migratory cells resulted in identical cellular responses to, but 10-fold lower humoral responses than, standard GI. Using an RU486-inducible system, we were able to measure responses generated by directly transfected LC. Our results indicate that direct transfection is a predominant pathway for LC Ag loading. The ability to regulate transgene expression with inducible DC-based vaccines demonstrates a new level of immunological control.

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Induction of antigen-specific immunosuppression by CD95L cDNA-transfected 'killer' dendritic cells

Cited by 150 publications

References 46 publications

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

Mature But Not Immature Fas Ligand (CD95L)-Transduced Human Monocyte-Derived Dendritic Cells Are Protected from Fas-Mediated Apoptosis and Can Be Used as Killer APC

Drug-Inducible, Dendritic Cell-Based Genetic Immunization

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