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Tumor-Derived Autophagosomes (DRibbles) Activate Human B Cells to Induce Efficient Antigen-Specific Human Memory T-Cell Responses.

ABSTRACT: We have reported that tumor-derived autophagosomes (DRibbles) were efficient carriers of tumor antigens and DRibbles antigens could be present by DRibbles-activated B cells to stimulate effect and naïve T cells in mice. However, the effect of DRibbles on human B cells remains unclear. Herein, we found that DRibbles can also efficiently induce proliferation and activation of human B cells and lead to the production of chemokines, cytokines and hematopoietic growth factors. We further demonstrated human B cells can effectively phagocytose DRibbles directly and cross-present DRibbles antigens to stimulate antigen-specific memory T cells. Furthermore, we found that membrane-bound high-mobility group B1 (HMGB1) on DRibbles was crucial for inducing human B cells activation. Therefore, these findings provide further evidence to promote the clinical application of B-DRibbles vaccines.

SUBMITTER: Ren H

PROVIDER: S-EPMC8187759 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Tumor-Derived Autophagosomes (DRibbles) Activate Human B Cells to Induce Efficient Antigen-Specific Human Memory T-Cell Responses.

Ren Hongyan H Zhang Tianyu T Wang Yongren Y Yao Qi Q Wang Ziyu Z Zhang Luyao L Wang Lixin L

Frontiers in immunology 20210526

We have reported that tumor-derived autophagosomes (DRibbles) were efficient carriers of tumor antigens and DRibbles antigens could be present by DRibbles-activated B cells to stimulate effect and naïve T cells in mice. However, the effect of DRibbles on human B cells remains unclear. Herein, we found that DRibbles can also efficiently induce proliferation and activation of human B cells and lead to the production of chemokines, cytokines and hematopoietic growth factors. We further demonstrated ...[more]

PMID: 34122437

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Project description:BackgroundAutophagy 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.MethodsDRibbles 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-?, IFN-? and IFN-?) 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.ResultsIn 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-? 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.ConclusionsDRibbles 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.

Dataset Information

Tumor-Derived Autophagosomes (DRibbles) Activate Human B Cells to Induce Efficient Antigen-Specific Human Memory T-Cell Responses.

Publications

Tumor-Derived Autophagosomes (DRibbles) Activate Human B Cells to Induce Efficient Antigen-Specific Human Memory T-Cell Responses.

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