Cross-presentation of dead-cell-associated antigens by DNGR-1+ dendritic cells contributes to chronic allograft rejection in mice
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Saidou Balam Rebecca Kesselring Eggenhofer Elke Stephanie Blaimer Katja Evert Matthias Evert Hans J Schlitt Edward K Geissler Janneke van Blijswijk Sonia Lee Caetano Reis e Sousa Stefan M Brunner Stefan Fichtner-FeiglAbstract
The purpose of this study was to elucidate whether DNGR-1-dependent cross-presentation of dead-cell-associated antigens occurs after transplantation and contributes to CD8+ T cell responses, chronic allograft rejection (CAR) and fibrosis. BALB/c or C57BL/6 hearts were heterotopically transplanted into wild type (WT), Clec9a-/- or Batf3-/- recipient C57BL/6 mice. Allografts were analysed for cell infiltration, CD8+ T cell activation, fibrogenesis and CAR using immunohistochemistry, Western blot, qRT2 -PCR and flow cytometry. Allografts displayed infiltration by recipient DNGR-1+ DCs, signs of CAR and fibrosis. Allografts in Clec9a-/- recipients showed reduced CAR (P<0.0001), fibrosis (P = 0.0137), CD8+ cell infiltration (P<0.0001) and effector cytokine levels compared to WT recipients. Batf3-deficiency greatly reduced DNGR-1+ DC-infiltration, CAR (P<0.0001) and fibrosis (P = 0.0382). CD8 cells infiltrating allografts of cytochrome c treated recipients, showed reduced production of CD8 effector cytokines (P<0.05). Further, alloreactive CD8+ T cell response in indirect pathway IFN-γ ELISPOT was reduced in Clec9a-/- recipient mice (P = 0.0283). Blockade of DNGR-1 by antibody, similar to genetic elimination of the receptor, reduced CAR (P = 0.0003), fibrosis (P = 0.0273), infiltration of CD8+ cells (P = 0.0006) and effector cytokine levels. DNGR-1-dependent alloantigen cross-presentation by DNGR-1+ DCs induces alloreactive CD8+ cells that induce CAR and fibrosis. Antibody against DNGR-1 can block this process and prevent CAR and fibrosis. This article is protected by copyright. All rights reserved.
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Journal European Journal of Immunology
Volume 50
Issue number 12
Pages 2041-2054
Available online
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Publisher website (DOI) 10.1002/eji.201948501
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Europe PubMed Central 32640051
Pubmed 32640051
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