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

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Cross-presentation of dead-cell-associated antigens by DNGR-1+ dendritic cells contributes to chronic allograft rejection in mice.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-07-08 , DOI: 10.1002/eji.201948501
Saidou Balam ₁ , Rebecca Kesselring ₁ , Elke Eggenhofer ₁ , Stephanie Blaimer ₁ , Katja Evert ₂ , Matthias Evert ₂ , Hans J Schlitt ₁ , Edward K Geissler ₁ , Janneke van Blijswijk ₃ , Sonia Lee ₃ , Caetano Reis e Sousa ₃ , Stefan M Brunner ₁ , Stefan Fichtner-Feigl _{1,

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Affiliation

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.

中文翻译：

DNGR-1 +树突状细胞交叉展示与死细胞相关的抗原有助于小鼠慢性异体移植排斥。

这项研究的目的是阐明是否在移植后发生死细胞相关抗原的DC NK凝集素组受体-1（DNGR-1）依赖性交叉呈递，并有助于CD8 ⁺ T细胞反应，慢性同种异体移植排斥反应（CAR ）和纤维化。将BALB / c或C57BL / 6心脏异位移植到WT，Clec9a ^-/-或Batf3 ^-/-受体C57BL / 6小鼠中。使用免疫组织化学，Western印迹，qRT ^2‐ PCR和流式细胞仪分析同种异体移植的细胞浸润，CD8 ⁺ T细胞活化，纤维生成和CAR 。同种异体移植物显示受者DNGR-1 ⁺ DC浸润，CAR征象和纤维化。Clec9a中的同种异体移植物^-/- 与WT受体相比，受体受体的CAR（p <0.0001），纤维化（P = 0.0137），CD8 ⁺细胞浸润（P <0.0001）和效应细胞因子水平降低。Batf3缺乏症大大减少了DNGR-1 ⁺ DC浸润，CAR（P <0.0001）和纤维化（P = 0.0382）。CD8细胞浸润同种异体细胞色素C处理的受体后，显示出CD8效应细胞因子的产生减少（P <0.05）。此外，在Clec9a ^-/-受体小鼠中，间接途径IFN-γELISPOT的同种反应性CD8 ⁺ T细胞应答减少（P= 0.0283）。抗体对DNGR-1的阻断作用与受体的遗传消除相似，降低了CAR（P = 0.0003），纤维化（P = 0.0273），CD8 ⁺细胞浸润（p = 0.0006）和效应细胞因子水平。DNGR-1 ⁺ DC依赖DNGR-1的同种异体抗原交叉呈递诱导诱导CAR和纤维化的同种异体CD8 ⁺细胞。DNGR-1抗体可以阻止该过程并防止CAR和纤维化。

更新日期：2020-07-08

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