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Follicular Helper T Cell Derived Exosomes Promote B Cell Proliferation and Differentiation in Antibody-Mediated Rejection after Renal Transplantation.

ABSTRACT: Follicular helper T cells (Tfh cells) are closely related to the occurrence and development of antibody-mediated rejection (AMR) after renal transplantation. Exosomes play a key role in the rejection after organ transplantation. However, whether Tfh-derived exosomes are involved in AMR has not been reported. We collected peripheral blood from 42 kidney transplant patients and found no significant differences in CD4+CXCR5+ and CD4+CXCR5+CXCR3+CCR6-exosomes between AMR and non-AMR groups, whereas the proportion of CD4+CXCR5+CXCR3-exosomes was significantly higher in AMR group than that in non-AMR group; CTLA-4 expression of CD4+CXCR5+exosomes was significantly lower in AMR group than that in non-AMR group. HLA-G expression was not significantly different between two groups. We further separated CD4+CXCR5+cells from patients by magnetic beads. Coculture experiments showed that Tfh cell-derived exosomes in AMR patients significantly promoted B cell proliferation and differentiation, compared with non-AMR group, the percentage of B cells and plasma cells increased by 87.52% and 110.2%, respectively. In conclusion, our study found that Tfh cell-derived exosomes could promote the proliferation and differentiation of B cells and they may play an important role in the development of AMR after renal transplantation.

SUBMITTER: Yang J

PROVIDER: S-EPMC6541933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Renal transplantation is currently the most effective treatment for end-stage renal disease. However, chronic antibody-mediated rejection (cABMR) remains a serious obstacle for the long-term survival of patients with renal transplantation and a problem to be solved. At present, the role and mechanism underlying immune factors such as T- and B- cell subsets in cABMR after renal transplantation remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood monocytes (PBMCs) from cABMR and control subjects was performed to define the transcriptomic landscape at single-cell resolution. A comprehensive scRNA-seq analysis was performed. The results indicated that most cell types in the cABMR patients exhibited an intense interferon response and release of proinflammatory cytokines. In addition, we found that the expression of MT-ND6, CXCL8, NFKBIA, NFKBIZ, and other genes were up-regulated in T- and B-cells and these genes were associated with pro-inflammatory response and immune regulation. Western blot and qRT-PCR experiments also confirmed the up-regulated expression of these genes in cABMR. GO and KEGG enrichment analyses indicated that the overexpressed genes in T- and B-cells were mainly enriched in inflammatory pathways, including the TNF, IL-17, and Toll-like receptor signaling pathways. Additionally, MAPK and NF-κB signaling pathways were also involved in the occurrence and development of cABMR. This is consistent with the experimental results of Western blot. Trajectory analysis assembled the T-cell subsets into three differentiation paths with distinctive phenotypic and functional prog rams. CD8 effector T cells and γδ T cells showed three different differentiation trajectories, while CD8_MAI T cells and naive T cells primarily had two differentiation trajectories. Cell-cell interaction analysis revealed strong T/B cells and neutrophils activation in cABMR. Thus, the study offers new insight into pathogenesis and may have implications for the identification of novel therapeutic targets for cABMR.

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Follicular Helper T Cell Derived Exosomes Promote B Cell Proliferation and Differentiation in Antibody-Mediated Rejection after Renal Transplantation.

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