Premium
Cross‐presentation of dead‐cell‐associated antigens by DNGR‐1 + dendritic cells contributes to chronic allograft rejection in mice
Author(s) -
Balam Saidou,
Kesselring Rebecca,
Eggenhofer Elke,
Blaimer Stephanie,
Evert Katja,
Evert Matthias,
Schlitt Hans J.,
Geissler Edward K.,
Blijswijk Janneke,
Lee Sonia,
Reis e Sousa Caetano,
Brunner Stefan M.,
FichtnerFeigl Stefan
Publication year - 2020
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201948501
Subject(s) - cd8 , fibrosis , t cell , biology , immunology , elispot , cytotoxic t cell , antigen , immune system , medicine , pathology , biochemistry , in vitro
Abstract 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‐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.