CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone vaccine activity against mouse melanoma.
CD204 suppresses large heat shock protein-facilitated priming of tumor antigen gp100-specific T cells and chaperone vaccine activity against mouse melanoma.
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DOI：
10.4049/jimmunol.1100703
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发表时间：
2011-09-15
期刊：
影响因子：
--
通讯作者：
Wang XY
中科院分区：
文献类型：
--
作者：
Qian J;Yi H;Guo C;Yu X;Zuo D;Chen X;Kane JM 3rd;Repasky EA;Subjeck JR;Wang XY
我们先前报道了清道夫受体A（SRA/CD 204），树突状细胞（DC）上的大的应激/热休克蛋白（HSP，例如，hsp 110和grp 170），减弱了由大的基于HSP的疫苗引起的抗肿瘤应答。在这里，我们表明，SRA/CD 204直接与外源性hsp 110相互作用，缺乏SRA/CD 204的结果在hsp 110的结合和内化的DC减少。然而，与野生型（WT）DC相比，用hsp 110或grp 170重建的gp 100伴侣复合物脉冲的SRA−/− DC显示出刺激黑素瘤抗原gp 100特异性幼稚T细胞的能力显著增加。当使用编码shRNA的慢病毒在DC中沉默SRA/CD 204时，获得了类似的结果。此外，热休克蛋白110刺激的SRA−/− DC产生更多的炎症细胞因子，与增加NF-κB活化相关，暗示SRA/CD 204的免疫抑制作用。免疫接种hsp 110-gp 100疫苗导致SRA−/−小鼠中gp 100特异性CD 8 + T细胞应答比WT小鼠更强。最后，SRA/CD 204缺失显著改善了hsp 110-gp 100疫苗在建立有B16黑色素瘤的小鼠中的治疗功效，这伴随着增强的CD 8 + T细胞的活化和肿瘤浸润。鉴于抗原递呈细胞上存在多种HSP结合清道夫受体，我们认为选择性清道夫受体与HSP的相互作用可能会导致高度不同的免疫后果。我们的研究结果为SRA/CD 204的免疫调节功能提供了新的见解，并对合理设计用于治疗癌症的蛋白抗原靶向重组伴侣疫苗具有重要意义。
We previously reported that scavenger receptor A (SRA/CD204), a binding structure on dendritic cells (DCs) for large stress/heat shock proteins (HSPs, e.g., hsp110 and grp170), attenuated an antitumor response elicited by large HSP-based vaccines. Here we show that SRA/CD204 interacts directly with exogenous hsp110 and lack of SRA/CD204 results in a reduction in the hsp110 binding and internalization by DCs. However, SRA−/− DCs pulsed with hsp110 or grp170-reconstituted gp100 chaperone complexes exhibit profoundly increased capability of stimulating melanoma antigen gp100-specific naïve T-cells compared to wild-type (WT) DCs. Similar results were obtained when SRA/CD204 was silenced in DCs using shRNAs-encoding lentiviruses. In addition, hsp110-stimulated SRA−/− DCs produced more inflammatory cytokines associated with increased NF-κB activation, implicating an immunosuppressive role of SRA/CD204. Immunization with the hsp110-gp100 vaccine resulted in a more robust gp100-specific CD8+ T cell response in SRA−/− mice than in WT mice. Lastly, SRA/CD204 absence markedly improved the therapeutic efficacy of the hsp110-gp100 vaccine in mice established with B16 melanoma, which was accompanied by enhanced activation and tumor infiltration of CD8+ T cells. Given the presence of multiple HSP-binding scavenger receptors on antigen-presenting cells, we propose that selective scavenger receptor interactions with HSPs may lead to highly distinct immunological consequences. Our findings provide new insights to the immune regulatory functions of SRA/CD204 and have important implications in the rational design of protein antigen-targeted recombinant chaperone vaccines for the treatment of cancer.
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