LAUSR

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, 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.