Opsonization of Apoptotic Cells by Autologous iC3b Facilitates Clearance by Immature Dendritic Cells, Down-regulates DR and CD86, and Up-regulates CC Chemokine Receptor 7

Verbovetski, Inna; Bychkov, Hila; Trahtemberg, Uriel; Shapira, Itzhak; Hareuveni, Mara; Ben‐Tal, Ofira; Kutikov, Ina; Gill, Oranit; Mevorach, Dror

doi:10.1084/jem.20020263

Cited by 232 publications

(252 citation statements)

References 48 publications

(61 reference statements)

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“…The suppression of proinflammatory cytokines induced by CR3 on DCs may be beneficial in these cases. CR3 triggering is often obtained using particulated systems such as RBC opsonized with iC3b (6,8). The ability to induce CR3 inhibitory effects using direct ligation via mAbs, as we achieved, is encouraging for its ready feasibility in testing this approach therapeutically.…”

Section: Discussionmentioning

confidence: 90%

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

Behrens

Sriram

Shivers

et al. 2007

The Journal of Immunology

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To activate T cells effectively, dendritic cells (DCs) must provide three separate signals, MHC-Ag, costimulatory molecules (such as CD80 and CD86), and proinflammatory cytokines (such as IL-12). These three signals are up-regulated in the presence of “danger signals” such as LPS or viral nucleic acids. Evidence suggests that DCs providing only the first two of these signals cannot successfully stimulate T cells. Apoptotic cells have been proposed to suppress DC immunogenicity through the ligation of apoptotic cell receptors. Complement receptor 3 (CR3) and CD36 have been suggested to be important in this process, although the mechanism by which this modulation occurs is still unclear. We demonstrate that ligation of CR3, but not CD36, directs DCs to increase surface MHC and costimulatory molecules, while suppressing inflammatory cytokine release. CR3 modulation of DCs does not require a type I IFN response, does not involve the specific regulation of the MyD88- or Toll/IL-1R domain-containing adaptor-inducing IFN-β-dependent TLR signaling pathways, and occurs even in the absence of danger signals. The functional outcome of this process is poor Ag-specific stimulation of CD4 and CD8 T cells by CR3-ligated DCs both in naive response as well as upon subsequent challenge with normal DCs. We propose that CR3 provides a “nondanger” signal that suppresses the stimulatory capacity of DCs.

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Section: Discussionmentioning

confidence: 90%

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

Behrens

Sriram

Shivers

et al. 2007

The Journal of Immunology

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“…Again microparticles were at least as effective as apoptotic cells. In this context, it is of interest that a reduced expression of MHC class II and CD86 has also been described with dendritic cells that were exposed to iC3b-coated apoptotic cells [29].…”

Section: Discussionmentioning

confidence: 98%

“…Microparticles exposed to serum are able to activate complement, resulting in a deposition of iC3b on their surface. It has previously been shown for apoptotic cells that complement activation plays an important role for their uptake by macrophages and immature dendritic cells [27][28][29]. Phosphatidylserine on apoptotic cells is at least partially involved in the activation of complement and contributes to the deposition of complement components like iC3b on the membrane surface [27,30,31].…”

Section: Discussionmentioning

confidence: 99%

Differential mechanisms of microparticle transfer toB cells and monocytes: anti‐inflammatory propertiesof microparticles

Köppler¹,

Cohen²,

Schlöndorff

et al. 2006

Eur J Immunol

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Microparticles are small vesicles released from the plasma membrane of various cell types independently of apoptosis or cell death, are transferred between cells, and carry membrane proteins from one cell to another. We have studied the mechanism of uptake of microparticles by monocytes and B cells. The transfer of microparticles to B cells was almost completely dependent on complement. Incubation of microparticles with serum resulted in opsonization of microparticles with the complement cleavage product iC3b. The subsequent transfer to B cells was mediated by the complement receptor CR2. The interaction between iC3b-opsonized microparticles and B cells reduced the activation of B cells as measured by expression of MHC class II, CD86 and CD25. In contrast, transfer of microparticles to monocytes was only partially complement dependent, but involved calcium and annexin V, and was found to change the cytokine profile of monocytes towards a reduced release of the pro-inflammatory cytokines GM-CSF and TNF-a and an increased release of the anti-inflammatory cytokine IL-10. These data show that microparticles are taken up by B cells and monocytes by different mechanisms and modulate the activation of monocytes and B cells towards an anti-inflammatory phenotype. Microparticles might be involved in counterbalancing pro-inflammatory signals arising from tissue injury or inflammation.

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“…Furthermore, the role of apoptosis in the induction or prevention of an immune response is still unclear. Indeed, some groups have demonstrated that the uptake of apoptotic cells by DC results in T cell tolerance [4][5][6]. Conversely, other groups have shown that DC that have phagocytosed apoptotic bodies from virus-infected cells can present viral antigens to cytotoxic T cells and induce a cytotoxic response [7,8].…”

Section: Introductionmentioning

confidence: 99%

Immunopotentiation of the antibody response against influenza HA with apoptotic bodies generated by rabies virus G-ERA protein-driven apoptosis

Mégret

Préhaud

Lafage

et al. 2005

Vaccine

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Apoptosis is considered to be a way of eliminating unwanted cells without causing major inflammation. Nevertheless, several lines of evidence show that apoptotic cell-derived antigens can be strong immunogens. The rabies virus glycoprotein G-ERA is an apoptotic molecule. We tested the ability of G-ERA to potentiate a B cell response against an exogenous antigen (influenza hemagglutinin, HA). We found that co-expression of G-ERA and HA in apoptotic bodies increased both the primary and memory HA-specific immune responses. The immunopotentiation of G-ERA is apoptosis-mediated but not necrosismediated. Our data indicate that G-ERA-mediated apoptosis might be useful to improve the immunogenicity of live vaccines.3

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Opsonization of Apoptotic Cells by Autologous iC3b Facilitates Clearance by Immature Dendritic Cells, Down-regulates DR and CD86, and Up-regulates CC Chemokine Receptor 7

Cited by 232 publications

References 48 publications

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

Complement Receptor 3 Ligation of Dendritic Cells Suppresses Their Stimulatory Capacity

Differential mechanisms of microparticle transfer toB cells and monocytes: anti‐inflammatory propertiesof microparticles

Immunopotentiation of the antibody response against influenza HA with apoptotic bodies generated by rabies virus G-ERA protein-driven apoptosis

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