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

European journal of immunology 2020 Dec

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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. © 2020 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Citation

Saidou Balam, Rebecca Kesselring, Elke Eggenhofer, 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. Cross-presentation of dead-cell-associated antigens by DNGR-1+ dendritic cells contributes to chronic allograft rejection in mice. European journal of immunology. 2020 Dec;50(12):2041-2054