eji.201948501.pdf (12.67 MB)

Cross-presentation of dead-cell-associated antigens by DNGR-1+ dendritic cells contributes to chronic allograft rejection in mice.

Download (12.67 MB)
journal contribution
posted on 07.01.2021, 09:11 by 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-Feigl
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.

Funding

Crick (Grant ID: 10136, Grant title: Reis e Sousa FC001136) European Research Council (Grant ID: 786674 - DCPOIESIS, Grant title: ERC 786674 - DCPOIESIS)

History