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Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103+ DCs-mediated CD8+ T cell responses.

ABSTRACT: Diabetic nephropathy (DN) as a kind of serious microvascular complication of Diabetes Mellitus (DM) usually causes the end-stage of renal disease (ESRD). Studies have demonstrated that CD103+ dendritic cells (DCs) exhibited a renal pathogenic effect in murine chronic kidney disease (CKD). Mesenchymal stem cells (MSCs) can alleviate DN and suppress the DCs maturation. To explore the role of CD103+ DCs and the potential mechanisms underlying MSCs-mediated protective effects in DN, we used bone marrow MSCs (BM-MSCs) to treat DN rats. MSCs transplantation considerably recovered kidney function and diminished renal injury, fibrosis and the population of renal CD103+ DCs in DN rat. The MSCs-treated DN rats had decreased mRNA expression levels of interleukin (IL)1?, IL6, tumour necrosis factor alpha (TNF-?), monocyte chemotactic protein 1 (MCP-1) and reduced CD8 T cell infiltration in the kidney. MSCs significantly down-regulated the genes expression of transcription factors (Basic leucine zipper transcriptional factor ATF-like 3, Batf3 and DNA-binding protein inhibitor ID-2, Id2) and FMS-like tyrosine kinase-3 (Flt3) which are necessary for CD103+ DCs development. The protective effect of MSCs may be partly related to their immunosuppression of CD8+ T cell proliferation and activation mediated by CD103+ DCs in the kidney of DN rats.

SUBMITTER: Zhang F

PROVIDER: S-EPMC7214166 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103+ DCs-mediated CD8+ T cell responses.

Zhang Fuping F Wang Chengshi C Wen Xin X Chen Yang Y Mao Ruiwen R Cui Danli D Li Lan L Liu Jingping J Chen Younan Y Cheng Jingqiu J Lu Yanrong Y

Journal of cellular and molecular medicine 20200413 10

Diabetic nephropathy (DN) as a kind of serious microvascular complication of Diabetes Mellitus (DM) usually causes the end-stage of renal disease (ESRD). Studies have demonstrated that CD103+ dendritic cells (DCs) exhibited a renal pathogenic effect in murine chronic kidney disease (CKD). Mesenchymal stem cells (MSCs) can alleviate DN and suppress the DCs maturation. To explore the role of CD103+ DCs and the potential mechanisms underlying MSCs-mediated protective effects i ...[more]

PMID: 32283569

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Project description:BackgroundImmune cell heterogenicity is known to determine the therapeutic response to cancer progression. Neoadjuvant chemoimmunotherapy (NACI) has shown clinical benefits in some patients with advanced head and neck squamous cell carcinoma (HNSCC), but the underlying mechanism behind this clinical response is unknown. The efficacy of NACI needs to be potentiated by identifying accurate biomarkers to predict clinical responses. Here, we attempted to identify molecules predicting NACI response in advanced HNSCC.MethodsWe performed combined single-cell RNA sequencing (scRNA-seq) and multiplex immunofluorescence (mIHC) staining with tumor samples derived from NACI-treated HNSCC patients to identify a new tumor-infiltrating cell (TIL) subtype, CD103+ CD8+ TILs, associated with clinical response, while both in vitro and in vivo assays were carried out to determine its antitumor efficiency. The regulatory mechanism of the CD103+ CD8+ TILs population was examined by performing cell-cell interaction analysis of the scRNA-seq data and spatial analysis of the mIHC images.ResultsWe established intratumoral CD103+ CD8+ TILs density as a determinant of NACI efficacy in cancers. Our scRNA-seq results indicated that the population of CD103+ CD8+ TILs was dramatically increased in the responders of NACI-treated HNSCC patients, while mIHC analysis confirmed the correlation between intratumoral CD103+ CD8+ TILs density and NACI efficacy in HNSCC patients. Further receiver operating characteristic curve analysis defined this TIL subset as a potent marker to predict patient response to NACI. Functional assays showed that CD103+ CD8+ TILs were tumor-reactive T cells, while programmed cell death protein-1 (PD-1) blockade enhanced CD103+ CD8+ TILs cytotoxicity against tumor growth in vivo. Mechanistically, targeting the triggering receptor expressed on myeloid cells 2-positive (TREM2+ ) macrophages might enhance the population of CD103+ CD8+ TILs and facilitate antitumor immunity during NACI treatment.ConclusionsOur study highlights the impact of intratumoral CD103+ CD8+ TILs density on NACI efficacy in different cancers, while the efforts to elevate its population warrant further clinical investigation.

Dataset Information

Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103+ DCs-mediated CD8+ T cell responses.

Publications

Mesenchymal stem cells alleviate rat diabetic nephropathy by suppressing CD103<sup>+</sup> DCs-mediated CD8<sup>+</sup> T cell responses.

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