Diese Publikation ist Teil des DEAL-Vertrags mit Wiley.
Zusammenfassung
The purpose of this study was to elucidate whether DC NK lectin group receptor-1 (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 WT, Clec9a(-/-), or Batf3(-/-)recipient C57BL/6 mice. ...
Zusammenfassung
The purpose of this study was to elucidate whether DC NK lectin group receptor-1 (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 WT, Clec9a(-/-), or Batf3(-/-)recipient C57BL/6 mice. Allografts were analyzed for cell infiltration, CD8(+)T cell activation, fibrogenesis, and CAR using immunohistochemistry, Western blot, qRT(2)-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-gamma 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.
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