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.
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 alpha (TNFalpha). 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 TNFalpha was added in combination with apoptotic neutrophils, the inhibitory effects were overcome to some extent.


CONCLUSIONS
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.
Clayton
Abigail R
AR
MRC Centre for Immune Regulation, University of Birmingham Medical School, Birmingham B15 2TT, UK.
Prue
Rebecca L
RL
Harper
Lorraine
L
Drayson
Mark T
MT
Savage
Caroline O S
CO
D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D018122:B7-1 Antigen / Q000096:biosynthesis*; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000096:biosynthesis*; D002455:Cell Division / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D008562:Membrane Glycoproteins