Fossum Even, Grødeland Gunnveig, Terhorst Dorothea, Tveita Anders A, Vikse Elisabeth, Mjaaland Siri, Henri Sandrine, Malissen Bernard, Bogen Bjarne
K.G. Jebsen Center for Influenza Vaccine Research, Institute of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway.
Eur J Immunol. 2015 Feb;45(2):624-35. doi: 10.1002/eji.201445080. Epub 2014 Dec 28.
Targeting antigens to cross-presenting dendritic cells (DCs) is a promising method for enhancing CD8(+) T-cell responses. However, expression patterns of surface receptors often vary between species, making it difficult to relate observations in mice to other animals. Recent studies have indicated that the chemokine receptor Xcr1 is selectively expressed on cross-presenting murine CD8α(+) DCs, and that the expression is conserved on homologous DC subsets in humans (CD141(+) DCs), sheep (CD26(+) DCs), and macaques (CADM1(+) DCs). We therefore tested if targeting antigens to Xcr1 on cross-presenting DCs using antigen fused to Xcl1, the only known ligand for Xcr1, could enhance immune responses. Bivalent Xcl1 fused to model antigens specifically bound CD8α(+) DCs and increased proliferation of antigen-specific T cells. DNA vaccines encoding dimeric Xcl1-hemagglutinin (HA) fusion proteins induced cytotoxic CD8(+) T-cell responses, and mediated full protection against a lethal challenge with influenza A virus. In addition to enhanced CD8(+) T-cell responses, targeting of antigen to Xcr1 induced CD4(+) Th1 responses and highly selective production of IgG2a antibodies. In conclusion, targeting of dimeric fusion vaccine molecules to CD8α(+) DCs using Xcl1 represents a novel and promising method for induction of protective CD8(+) T-cell responses.
将抗原靶向交叉呈递树突状细胞（DCs）是增强CD8(+) T细胞反应的一种有前景的方法。然而，表面受体的表达模式在不同物种间常常有所不同，这使得将小鼠中的观察结果应用于其他动物变得困难。最近的研究表明，趋化因子受体Xcr1在交叉呈递的小鼠CD8α(+) DCs上选择性表达，并且在人类（CD141(+) DCs）、绵羊（CD26(+) DCs）和猕猴（CADM1(+) DCs）的同源DC亚群上表达保守。因此，我们测试了使用与Xcr1唯一已知配体Xcl1融合的抗原将抗原靶向交叉呈递DCs上的Xcr1是否能增强免疫反应。与模型抗原融合的二价Xcl1特异性结合CD8α(+) DCs并增加抗原特异性T细胞的增殖。编码二聚体Xcl1-血凝素（HA）融合蛋白的DNA疫苗诱导细胞毒性CD8(+) T细胞反应，并介导对甲型流感病毒致死性攻击的完全保护。除了增强CD8(+) T细胞反应外，将抗原靶向Xcr1还诱导CD4(+) Th1反应和IgG2a抗体的高度选择性产生。总之，使用Xcl1将二聚体融合疫苗分子靶向CD8α(+) DCs代表了一种诱导保护性CD8(+) T细胞反应的新颖且有前景的方法。
