Mediators Involved in the Immunomodulatory Effects of Apoptotic Cells

Saas, Philippe; Bonnefoy, Francis; Kury-Paulin, S; Kleinclauss, F.; Perruche, Sylvain

doi:10.1097/01.tp.0000269113.59857.d6

Cited by 30 publications

(30 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have found that apoptotic cells exhibit a dramatic immunosuppressive effect in vivo (6,43,44). Our studies with heart transplantation showed that a single injection of apoptotic cells could extend successful engraftment for Ͼ40 days on the average.…”

Section: Discussionmentioning

confidence: 68%

Apoptotic Cells Induce Immunosuppression through Dendritic Cells: Critical Roles of IFN-γ and Nitric Oxide

Ren¹,

Zhao³

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Apoptotic cells induce immunosuppression through unknown mechanisms. To identify the underlying molecular mediators, we examined how apoptotic cells induce immunoregulation by dendritic cells (DC). We found that administration of DC exposed to apoptotic cells (DCap) strongly inhibited expansion of lymphocytes in draining lymph nodes (dLNs) in vivo and subsequent antigen‐specific activation of dLN lymphocytes ex vivo. Unexpectedly, DCap supported T cell activation to a similar extent as normal DC in vitro, leading to proliferation and IL‐2 production, except DCap did not support T cell production of IFNgamma. Surprisingly, when DCap were co‐cultured with normal DC, they completely lost their ability to support T cell activation, an effect reversed by anti‐IFNgamma or inhibitors of inducible nitric oxide synthase (iNOS). As expected, exposure to apoptotic cells rendered DCap capable of producing much more nitric oxide (NO) in response to exogenous IFNgamma than normal DC. Furthermore, DCap from iNOS−/− or IFNgammaR1−/− mice were not inhibitory. Therefore, the IFNgamma‐induced production of NO by apoptotic cell‐sensitized DC plays a key role in apoptotic cell‐mediated immunosuppression.

show abstract

Section: Discussionmentioning

confidence: 68%

Apoptotic Cells Induce Immunosuppression through Dendritic Cells: Critical Roles of IFN-γ and Nitric Oxide

Ren¹,

Zhao³

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In contrast to PDC isolated from healthy volunteers or to the GEN2.2 PDC cell line, EMP did not induce significant Mo-DC maturation and, in this setting, reduced lipopolysaccharide-induced IL-12 secretion, as observed after incubation with apoptotic cells. 9,38 Furthermore, microparticles derived from activated T cells or platelets did not induce PDC maturation. Lastly, PDC maturation induced by EMP required an active uptake mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Among the various circulating microparticles, platelet-derived microparticles are the most abundant in the bloodstream, representing between 70 to 90% of circulating microparticles in healthy subjects. 8 As shown for apoptotic bodies 9 -another form of cell dust or debris, tumor-or fibroblast-derived microparticles captured by monocytes may induce regulatory cytokine secretion. 10 In addition, microparticles from activated T cells can deliver differentiation signals to stem cells.…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell-derived microparticles induce plasmacytoid dendritic cell maturation: potential implications in inflammatory diseases

Angelot¹,

Seillès²,

Biichlé³

et al. 2009

Haematologica

View full text Add to dashboard Cite

BackgroundIncreased circulating endothelial microparticles, resulting from vascular endothelium dysfunction, and plasmacytoid dendritic cell activation are both encountered in common inflammatory disorders. The aim of our study was to determine whether interactions between endothelial microparticles and plasmacytoid dendritic cells could contribute to such pathologies. Design and MethodsMicroparticles generated from endothelial cell lines, platelets or activated T cells were incubated with human plasmacytoid dendritic cells sorted from healthy donor blood or with monocyte-derived dendritic cells. Dendritic cell maturation was evaluated by flow cytometry, cytokine secretion as well as naive T-cell activation and polarization. Labeled microparticles were also used to study cellular interactions. ResultsEndothelial microparticles induced plasmacytoid dendritic cell maturation. In contrast, conventional dendritic cells were resistant to endothelial microparticle-induced maturation. In addition to upregulation of co-stimulatory molecules, endothelial microparticlematured plasmacytoid dendritic cells secreted inflammatory cytokines (interleukins 6 and 8, but no interferon-α) and also induced allogeneic naive CD4 + T cells to proliferate and to produce type 1 cytokines such as interferon-γ and tumor necrosis factor-α. Endothelial microparticle endocytosis by plasmacytoid dendritic cells appeared to be required for plasmacytoid dendritic cell maturation. Importantly, the ability of endothelial microparticles to induce plasmacytoid dendritic cells to mature was specific as microparticles derived from activated T cells or platelets (the major source of circulating microparticules in healthy subjects) did not induce such plasmacytoid dendritic cell maturation. ConclusionsOur data show that endothelial microparticles specifically induce plasmacytoid dendritic cell maturation and production of inflammatory cytokines. This novel activation pathway may be implicated in various inflammatory disorders and endothelial microparticles could be an important immunmodulatory therapeutic target.

show abstract

“…A poptotic cells exert immunomodulatory properties (1)(2)(3). This occurs through the release of immunosuppressive cytokines by apoptotic cells themselves during the apoptotic process (4) as well as indirectly via cells uptaking apoptotic cells (5,6).…”

mentioning

confidence: 99%

Plasmacytoid Dendritic Cells Play a Major Role in Apoptotic Leukocyte-Induced Immune Modulation

Bonnefoy

Perruche

Couturier

et al. 2011

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Several APCs participate in apoptotic cell-induced immune modulation. Whether plasmacytoid dendritic cells (PDCs) are involved in this process has not yet been characterized. Using a mouse model of allogeneic bone marrow engraftment, we demonstrated that donor bone marrow PDCs are required for both donor apoptotic cell-induced engraftment and regulatory T cell (Treg) increase. We confirmed in naive mice receiving i.v. syngeneic apoptotic cell infusion that PDCs from the spleen induce ex vivo Treg commitment. We showed that PDCs did not interact directly with apoptotic cells. In contrast, in vivo macrophage depletion experiments using clodronate-loaded liposome infusion and coculture experiments with supernatant from macrophages incubated with apoptotic cells showed that PDCs required macrophage-derived soluble factors—including TGF-β—to exert their immunomodulatory functions. Overall, PDCs may be considered as the major APC involved in Treg stimulation/generation in the setting of an immunosuppressive environment obtained by apoptotic cell infusion. These findings show that like other APCs, PDC functions are influenced, at least indirectly, by exposure to blood-borne apoptotic cells. This might correspond with an additional mechanism preventing unwanted immune responses against self-antigens clustered at the cell surface of apoptotic cells occurring during normal cell turnover.

show abstract

Mediators Involved in the Immunomodulatory Effects of Apoptotic Cells

Cited by 30 publications

References 29 publications

Apoptotic Cells Induce Immunosuppression through Dendritic Cells: Critical Roles of IFN-γ and Nitric Oxide

Apoptotic Cells Induce Immunosuppression through Dendritic Cells: Critical Roles of IFN-γ and Nitric Oxide

Endothelial cell-derived microparticles induce plasmacytoid dendritic cell maturation: potential implications in inflammatory diseases

Plasmacytoid Dendritic Cells Play a Major Role in Apoptotic Leukocyte-Induced Immune Modulation

Contact Info

Product

Resources

About