In:
European Journal of Immunology, Wiley, Vol. 50, No. 12 ( 2020-12), p. 2041-2054
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.
Type of Medium:
Online Resource
ISSN:
0014-2980
,
1521-4141
DOI:
10.1002/eji.201948501
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
1491907-2
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