Dendritic cell maturation is induced by mycoplasma infection but not by necrotic cells

Salio, Mariolina; Cerundolo, Vincenzo; Lanzavecchia, Antonio

doi:10.1002/1521-4141(200002)30:2<705::aid-immu705>3.0.co;2-p

Cited by 85 publications

(51 citation statements)

References 8 publications

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“…Immature DCs are capable of efficiently phagocytosing both apoptotic and necrotic cells (7,9,14). This study is the first to provide direct evidence that immature human monocyte-derived DCs can ingest human apoptotic and necrotic neutrophils.…”

Section: Discussionmentioning

confidence: 72%

“…In contrast, Salio et al found that neither necrotic nor apoptotic melanoma cell lines induce human DC maturation (14). A further level of complexity has been added by the suggestion that even without additional maturation signals, high numbers of apoptotic cells (at a ratio of 5 apoptotic cells to 1 DC) are capable of inducing DC maturation and the presentation of intracellular antigens from these apoptotic cells, whereas low numbers of apoptotic cells are disposed of in a noninflammatory manner (15).…”

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confidence: 88%

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Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis

Clayton¹,

Prue²,

Harper³

et al. 2003

Arthritis & Rheumatism

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Objective. There is a breakdown of tolerance to neutrophil components during systemic vasculitis, which is marked by autoantibodies and T cells with specificity for proteinase 3 or myeloperoxidase, expressed on the surface of apoptotic neutrophils. This study was undertaken to investigate the effects of human apoptotic and necrotic neutrophils on human dendritic cell (DC) phenotype and ability to stimulate allogeneic T cell proliferation.Methods. DCs were generated from human peripheral blood mononuclear cells and allowed to interact with human apoptotic and necrotic neutrophils in the presence or absence of tumor necrosis factor ␣ (TNF␣). Effects on DC phenotype and ability to stimulate T cell proliferation were observed.Results. Immature DCs engulfed apoptotic and necrotic neutrophils, resulting in up-regulation of CD83 and class II major histocompatibility complex molecules, but down-regulation of CD40, CD80, and CD86, and a decreased ability to stimulate T cell proliferation. When TNF␣ was added in combination with apoptotic neutrophils, the inhibitory effects were overcome to some extent.Conclusion. Our results suggest that DC uptake of apoptotic or necrotic neutrophils alone does not shift the immune response from tolerance to autoimmunity in systemic vasculitis. However, cytokines found at sites of inflammation in vasculitis patients may act as maturation factors for DCs, and in combination with apoptotic neutrophils, may lead to an autoimmune phenotype.

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 88%

Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis

Clayton¹,

Prue²,

Harper³

et al. 2003

Arthritis & Rheumatism

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“…Also, macrophages have been described as acquiring antigen from heat shock protein-peptide complexes (30). It has also been observed by some (12), but not other labs (14), that when dendritic cells are exposed to necrotic cells they are stimulated to mature and become more immunostimulatory. These previously described phenomena are clearly distinct from the present report because they are acting locally at the site of cell damage, whereas we observe a systemic effect.…”

Section: Discussionmentioning

confidence: 93%

“…Through this process, antigen-presenting cells (APCs) would efficiently acquire and present antigens from dying cells to T lymphocytes. In addition, some (11,13) but not other (14) studies find that dying cells can also stimulate dendritic cells to mature. Outside of these studies, the danger hypothesis remains largely untested.…”

mentioning

confidence: 99%

Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses

Shi

Zheng

Rock

2000

Proc. Natl. Acad. Sci. U.S.A.

206

178

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General immunostimulants (adjuvants) are essential for generating immunity to many antigens. In bacterial infections, adjuvants are provided by components of the microorganism, e.g., lipopolysaccharide. However, it is unclear what provides the adjuvant effect for immune responses that are generated to tumors and many viruses. Here we show that cell injury and death of tumor or even normal cells provide a potent adjuvant effect for the stimulation of cytotoxic T lymphocyte responses. This adjuvant activity is constitutively present in the cytoplasm of cells and is increased in the cytoplasm of cells dying by apoptosis. The release of these components stimulates immune responses both locally and at a distance, and provides a simple mechanism to alert the immune system to potential danger in almost all pathological situations.I mmunologists have long known that to elicit optimal antibody or T cell immune responses antigens must be admixed with adjuvants such as killed bacteria or components of their cell wall (1, 2). It is likely that adjuvants work by activating cells of the innate immune system (e.g., macrophages, natural killer cells, and dendritic cells) to become more stimulatory and to produce cytokines and inflammatory mediators, which, in turn, upregulate many of the components that are needed to stimulate lymphocyte responses. In the absence of adjuvants, lymphocytes may fail to respond to an immunization or even be tolerized.Janeway (1-3) hypothesized that cells of the innate immune system would have receptors for unique components of microbial pathogens, which he termed pathogen-associated molecular patterns (PAMPs); these would allow a self-nonself discrimination and stimulate initial immune responses. As predicted, such receptors were identified in Drosophila (e.g., the toll receptor family; refs. 2 and 4) and more recently in mammals (5-8). Some of these receptors recognize PAMPs of bacteria whereas others react with unique molecular features of fungi. Engagement of PAMP receptors stimulates cells of the innate immune system, and this is thought to be the underlying mechanism of action of many microbial adjuvants.The immune system continually monitors tissues for infections with microbes and cancerous cells and must respond rapidly to successfully eliminate these threats. The adjuvant properties of bacteria and some viruses (e.g., double-stranded RNA) promote this process, allowing the generation of robust immune responses in natural infections (1, 2). However, it has been unclear what, if anything, provides an adjuvant effect for immune responses to tumors and other viruses. These pathogens lack any obvious source of PAMPs to stimulate innate immune responses. Nevertheless, immune responses are generated to tumors and viruses, implying that an adjuvant effect is somehow provided.On theoretical grounds, Matzinger (9, 10) has proposed that dying cells might provide a signal that alerts the immune system to danger. Recently, it has been shown in vitro that dying cells are recognized and avidly internali...

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“…36,41 However, in other reports, immature DCs were not matured after coculturing with tumor cell lysate or supernatant of necrotic cells alone. [42][43][44] To reconcile these contradictory results, Salio et al 43 and Somersan et al 37 have suggested that DCs are triggered to maturation not simply by the death of surrounding cells, but also by other coexisting stimulatory signals. These factors include inflammatory cytokines, 42 heat-shock proteins released by dead cells, 37 and microbial materials (e.g., mycoplasma) contained in the cell lysate.…”

Section: Discussionmentioning

confidence: 99%

Concurrent delivery of tumor antigens and activation signals to dendritic cells by irradiated CD40 ligand-transfected tumor cells resulted in efficient activation of specific CD8+ T cells

Liu

Cheng

et al. 2003

Cancer Gene Ther

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To improve the efficacy of tumor cell-based and dendritic cell (DC)-based cancer vaccines, this study explored the potential of a new cancer vaccine strategy, that is, the use of CD40 ligand-transfected tumor (CD40L-tumor) cells to simultaneously deliver both tumor-derived antigens (Ag) and maturation stimuli to DCs. Materials from frozen/thawed or irradiated human tumor cells, with or without surface CD40L, were internalized efficiently by immature DCs after coincubation. However, during the internalization process, only coculturing with irradiated CD40L-tumor cells resulted in concurrent, optimal DC maturation and production of proinflammatory chemokines and pro-Th1 cytokines, such as IL-6, IL-8, IL-12, IFN-g, and TNF-a. These activated DCs were the most potent cells to support the growth of CD8 þ , IFN-g-producing T cells, and to process tumor Ag for the generation of specific cytotoxic T cells in vitro. Animals vaccinated with irradiated CD40L-tumor cell-pulsed DCs were better protected against subsequent challenge of a weakly immunogenic tumor cell line than animals vaccinated with irradiated CD40L-tumor cells alone. Thus, our results strongly support the future clinical application of using DCs pulsed with irradiated CD40L-tumor cells as a cancer vaccine.

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Dendritic cell maturation is induced by mycoplasma infection but not by necrotic cells

Cited by 85 publications

References 8 publications

Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis

Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis

Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses

Concurrent delivery of tumor antigens and activation signals to dendritic cells by irradiated CD40 ligand-transfected tumor cells resulted in efficient activation of specific CD8+ T cells

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