Myeloid-derived suppressor cells in transplantation tolerance induction

Cao, Peng; Sun, Zejia; Chen, Feng; Zhang, Jiandong; Zhang, Feilong; Wang, Wei; Zhao, Yong

doi:10.1016/j.intimp.2020.106421

Cited by 14 publications

(9 citation statements)

References 107 publications

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“…MDSC is a group of heterogeneous cells derived from bone marrow, which have the ability to significantly inhibit immune cell response ( 36 ). MDSC can induce transplantation immune tolerance by inhibiting antigen nonspecific T cells and promoting Treg proliferation ( 37 ). After renal transplantation, M-MDSC in peripheral blood increased immediately, and inhibited the proliferation and effect of CD4+ T and CD8+ T cells, which was conducive to graft survival ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

Landscape of Immune Cells Heterogeneity in Liver Transplantation by Single-Cell RNA Sequencing Analysis

et al. 2022

Front. Immunol.

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Rejection is still a critical barrier to the long-term survival of graft after liver transplantation, requiring clinicians to unveil the underlying mechanism of liver transplant rejection. The cellular diversity and the interplay between immune cells in the liver graft microenvironment remain unclear. Herein, we performed single-cell RNA sequencing analysis to delineate the landscape of immune cells heterogeneity in liver transplantation. T cells, NK cells, B cells, and myeloid cell subsets in human liver and blood were enriched to characterize their tissue distribution, gene expression, and functional modules. The proportion of CCR6+CD4+ T cells increased within an allograft, suggesting that there are more memory CD4+ T cells after transplantation, in parallel with exhausted CTLA4+CD8+ T and actively proliferating MKI67+CD8+ T cells increased significantly, where they manifested heterogeneity, distinct function, and homeostatic proliferation. Remarkably, the changes of CD1c+ DC, CADM+ DC, MDSC, and FOLR3+ Kupffer cells increase significantly, but the proportion of CD163+ Kupffer, APOE+ Kupffer, and GZMA+ Kupffer decreased. Furthermore, we identified LDLR as a novel marker of activated MDSC to prevent liver transplant rejection. Intriguingly, a subset of CD4+CD8+FOXP3+ T cells included in CTLA4+CD8+ T cells was first detected in human liver transplantation. Furthermore, intercellular communication and gene regulatory analysis implicated the LDLR+ MDSC and CTLA4+CD8+ T cells interact through TIGIT-NECTIN2 signaling pathway. Taken together, these findings have gained novel mechanistic insights for understanding the immune landscape in liver transplantation, and it outlines the characteristics of immune cells and provides potential therapeutic targets in liver transplant rejection.

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Section: Discussionmentioning

confidence: 99%

Landscape of Immune Cells Heterogeneity in Liver Transplantation by Single-Cell RNA Sequencing Analysis

et al. 2022

Front. Immunol.

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“…Successful allograft transplantation is constantly plagued by the challenge of acute and chronic cell-mediated allograft rejection. This process is generally mediated by indirect or direct forms of antigen recognition and activated T-cell response ( 1 – 3 ). T cells respond to foreign (allogeneic) MHC molecules in the same way as to any foreign proteins, which include cytokine secretion, cell proliferation as well as differentiation.…”

Section: Introductionmentioning

confidence: 99%

Mettl14-mediated m6A modification enhances the function of Foxp3+ regulatory T cells and promotes allograft acceptance

Liu

Yuan²,

Zhou³

et al. 2022

Front. Immunol.

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N6-methyladenosine (m6A), the most prevalent form of internal mRNA modification, is extensively involved in Treg cells differentiation and function. However, the involvement of m6A in functional Treg cells for transplantation tolerance remains to be elucidated. By using an experimental transplantation mouse model, we found that m6A levels in Treg cells were altered during the induction of transplant tolerance by performing a dot blotting assay. Subsequently, we used the heterogenic Treg-specific Mettl14 knockout mice (Foxp3-Mettl14f/+ cKO) to reduce METTL14 expression and performed islets allograft transplantation. Our result revealed that reduced expression of METTL14 prevented Treg cells expansion and promoted the infiltration of CD4+ and CD8+ T cells around the allograft, which led to rapid allograft rejection in Foxp3-Mettl14f/+ cKO mice. The expression of regulatory cytokines including IL-10 and TGF-β was significantly decreased in Foxp3-Mettl14f/+ cKO mice, and the suppressive function of Treg cells was also abrogated. In addition, an analysis of RNA-seq data revealed that the SOCS family (SOCS1, SOCS2 and SOCS3) is the subsequent signaling pathway affected by the METTL14 mediated m6A modification in Treg cells to modulate the suppressive function after transplantation. Taken together, our study showed for the first time that the METTL14-mediated m6A modification is essential for the suppressive function of Treg cells in transplantation and may serve as a regulatory element of Treg cell-based therapy in transplant medicine.

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“…For instance, it has been found that the number of Tregs increased significantly and TGF-β + GM-CSF–induced MDSCs can promote their expansion both under in vitro and in vivo conditions. Several studies also found that in vitro -induced MDSCs could promote expansion of Tregs not only in skin graft but also in other organ transplantation, such as corneal, islets, kidney, and heart transplantation ( 45 ). In the present study, we found the adoptive transfer of GM-CSF + TGF-β–induced MDSCs could promote expansion of MDSCs in recipient mice.…”

Section: Discussionmentioning

confidence: 99%

TGF-β Enhances Immunosuppression of Myeloid-Derived Suppressor Cells to Induce Transplant Immune Tolerance Through Affecting Arg-1 Expression

et al. 2022

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Myeloid-derived suppressor cells (MDSCs) are a class of heterogeneous myeloid cells, which play an important role in immunosuppression. We intended to find an effective method that can produce MDSCs with significantly better efficiency and promote immune tolerance for transplant rejection through cell therapy. It has been reported that granulocyte and macrophage colony-stimulating factor (GM-CSF) could induce MDSCs in vitro to cause immunosuppression. In the present study, transforming growth factor β (TGF-β) was added to the induction system, and flow cytometry analysis was used to detect the phenotypes of induced MDSCs. Their potential immunosuppressive function and mechanisms were determined by co-culturing MDSCs with stimulated T cells in vitro and transferring MDSCs to the skin grafted C57BL/6J mouse models in vivo. It was found that the addition of TGF-β could effectively cause bone marrow cells to differentiate into a group of cells with stronger immunosuppressive functions, thereby inhibiting the proliferation of stimulated T cells. The population of CD11b+Gr-1+ MDSCs also increased significantly as compared with GM-CSF alone treatment. While detecting for immunosuppressive effectors, we found that expression of arginase 1 (Arg-1) was significantly upregulated in these MDSCs, and inhibitor of Arg-1 significantly suppressed their immunosuppressive capabilities. Moreover, an adoptive transfer of these cells significantly prolonged survival of allo-skin and improved immune tolerance in vivo. These findings indicated that TGF-β + GM-CSF could serve as an effective and feasible method to induce powerful immunosuppressive MDSCs in vitro. Thus, TGF-β + GM-CSF–induced MDSCs may have a promising role in prevention of the graft rejection.

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Myeloid-derived suppressor cells in transplantation tolerance induction

Cited by 14 publications

References 107 publications

Landscape of Immune Cells Heterogeneity in Liver Transplantation by Single-Cell RNA Sequencing Analysis

Landscape of Immune Cells Heterogeneity in Liver Transplantation by Single-Cell RNA Sequencing Analysis

Mettl14-mediated m6A modification enhances the function of Foxp3+ regulatory T cells and promotes allograft acceptance

TGF-β Enhances Immunosuppression of Myeloid-Derived Suppressor Cells to Induce Transplant Immune Tolerance Through Affecting Arg-1 Expression

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