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

Abstract

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.

Polymorphonuclear neutrophils deliver activation signals and antigenic molecules to dendritic cells: a new link between leukocytes upstream of T lymphocytes

“…The inability of apoptotic PMNs to activate DCs shown here is consistent with the reported capacity of such PMNs to elicit down-regulation of costimulatory molecules on DCs [36]. We found that CD40-increased expression appears to be mediated by soluble factors released by the PMNs, whereas HLA-DR and CD86 increase on DCs requires direct contact with PMNs.…”

Spontaneous or Mycobacterium tuberculosis‐induced apoptotic neutrophils exert opposite effects on the dendritic cell‐mediated immune response

“…In line with this, PMNapo reduce the antigen-presenting capabilities of DC in healthy PPD + controls as well as in TB patients, which is a clear indication of the presence of a memory Mtb-specific immune response. Nevertheless, our results showing that PMNapo reduce but not abrogate the DC-specific response against Mtb are in contrast with those observed with MLR assay [22], which is critically dependent on the surface expression of HLA-DR and CD86 molecules on DC, thus, minimal changes in these parameters could be dramatically reflected in the results. Interestingly, while lower numbers of PPD + -DC induce specific lymphocyte proliferation, higher numbers of DC were needed to achieve the maximum response in TB patients.…”

“…Besides, as we herein demonstrate, supernatants from PMN Mtb do induce maturation in DC, which could be ascribed to TNF-a and IL-1b secreted during the process of Mtb-induced PMN apoptosis, as we have previously observed [12], the cytokines known to trigger DC maturation [22,24]. Hence, PMN…”

“…It has been previously demonstrated that both viable and PMNapo could modulate DC maturation [21][22][23][24]. Therefore, we examined whether PMN that underwent spontaneous apoptosis (PMNapo) could affect Mtbinduced maturation of iDC in culture.…”

Expression of dendritic cell markers on cultured neutrophils and its modulation by anti-apoptotic and pro-apoptotic compounds

“…The innate immunity may be terminated after the phagocytosis of apoptotic neutrophils but apoptotic neutrophils might also contribute the development of adaptive immunity because bacteria and bacterial products in the inflammatory loci may be cross-presented by macrophages or DCs phagocytosing apoptotic neutrophils (van Gisbergen et al, 2005). It was reported that the uptake of apoptotic neutrophils by DCs leads to the enhanced expression of CD83 and MHC-II on the DCs but a reduced capacity of DCs to stimulate mixed leukocyte reaction (Clayton et al, 2003). Positive staining of CD83 by an immunohistochemical assay in the inflammatory sites might involve both aged and apoptotic neutrophils (Iking-Konert et al, 2002).…”