Cross-presentation of viral antigens in dribbles leads to efficient activation of virus-specific human memory t cells

被引:26
|
作者
Ye, Wei [1 ,2 ,3 ]
Xing, Yun [3 ,4 ]
Paustian, Christopher [5 ]
van de Ven, Rieneke [5 ]
Moudgil, Tarsem [5 ]
Hilton, Traci L. [6 ]
Fox, Bernard A. [5 ,7 ,8 ]
Urba, Walter J. [9 ]
Zhao, Wei [1 ,2 ]
Hu, Hong-Ming [1 ,2 ,3 ]
机构
[1] Southeast Univ, Sch Med, Nanjing 210009, Jiangsu, Peoples R China
[2] Southeast Univ, Sch Med, Affiliated Hosp 2, Canc Res & Biotherapy Ctr, Nanjing 210003, Jiangsu, Peoples R China
[3] Providence Canc Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Canc Immunobiol, Portland, OR USA
[4] China Pharmaceut Univ, Sch Life Sci & Technol, Minigene Pharm Lab, Nanjing 210009, Jiangsu, Peoples R China
[5] Providence Canc Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Mol & Tumor Immunol, Portland, OR USA
[6] UbiVac, Portland, OR USA
[7] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97201 USA
[8] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA
[9] Providence Canc Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Portland, OR USA
基金
中国国家自然科学基金;
关键词
Autophagosome; Cross-presentation; Immunological monitoring; Immunotherapy biomarker; Viral vaccine; Cancer vaccine; Memory antigen-specific T cells; Proteasome; DENDRITIC CELLS; IMMUNE-RESPONSES; AUTOPHAGOSOME; LYMPHOCYTES; VACCINATION; INTERFERON; HEALTH; ASSAYS; DCS;
D O I
10.1186/1479-5876-12-100
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Background: Autophagy regulates innate and adaptive immune responses to pathogens and tumors. We have reported that autophagosomes derived from tumor cells after proteasome inhibition, DRibbles (Defective ribosomal products in blebs), were excellent sources of antigens for efficient cross priming of tumor-specific CD8(+) T cells, which mediated regression of established tumors in mice. But the activity of DRibbles in human has not been reported. Methods: DRibbles or cell lysates derived from HEK293T or UbiLT3 cell lines expressing cytomegalovirus (CMV) pp65 protein or transfected with a plasmid encoding dominant HLA-A2 restricted CMV, Epstein-Barr virus (EBV), and Influenza (Flu) epitopes (CEF) were loaded onto human monocytes or PBMCs and the response of human CMV pp65 or CEF antigen-specific CD4(+) and CD8(+) memory T cells was detected by intracellular staining. The effect of cytokines (GM-CSF, IL-4, IL-12, TNF-alpha, IFN-alpha and IFN-gamma) TLR agonists (Lipopolysaccharide, Polyinosinic-polycytidylic acid (poly(I:C), M52-CpG, R848, TLR2 ligand) and CD40 ligand on the cross-presentation of antigens contained in DRibbles or cell lysates was explored. Results: In this study we showed that purified monocytes, or human PBMCs, loaded with DRibbles isolated from cells expressing CMV or CEF epitopes, could activate CMV- or CEF-specific memory T cells. DRibbles were significantly more efficient at stimulating CD8(+) memory T cells compared to cell lysates expressing the same antigenic epitopes. We optimized the conditions for T-cell activation and IFN-gamma production following direct loading of DRibbles onto PBMCs. We found that the addition of Poly(I:C), CD40 ligand, and GM-CSF to the PBMCs together with DRibbles significantly increased the level of CD8(+) T cell responses. Conclusions: DRibbles containing specific viral antigens are an efficient ex vivo activator of human antigen-specific memory T cells specific for those antigens. This function could be enhanced by combining with Poly(I:C), CD40 ligand, and GM-CSF. This study provides proof-of-concept for applying this strategy to activate memory T cells against other antigens, including tumor-specific T cells ex vivo for immunological monitoring and adoptive immunotherapy, and in vivo as vaccines for patients with cancer.
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页数:12
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