CD99-Dependent Expansion of Myeloid-Derived Suppressor Cells and Attenuation of Graft-Versus-Host Disease

Park, Hyojin; Byun, Dahye; Lee, An Hi; Kim, Ju Hyun; Ban, Young Larn; Araki, Masatake; Araki, Kimi; Yamamura, Ken Ichi; Kim, Inho; Park, Seong Hoe; Jung, Kyeong Cheon

doi:10.1007/s10059-012-2227-z

Cited by 6 publications

(6 citation statements)

References 34 publications

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“…To elucidate the mechanisms by which CD99 promotes self-renewal in HSCs, we evaluated hematopoietic stem and progenitor (HSPC) frequencies and blood counts in CD99-deficient mice generated by gene trapping ( B6-Cd99 Gt(pU-21T)44lmeg , referred to hereafter as CD99 Gt/Gt)(Park et al, 2012). We confirmed the absence of CD99 protein expression in T-cells from CD99 Gt/Gt mice by flow cytometry, given that T-cells exhibit uniformly high levels of CD99 expression ( Fig.1A ).…”

Section: Resultsmentioning

confidence: 99%

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis

Huang

Kapti

et al. 2023

Preprint

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Blood production is sustained by hematopoietic stem cells (HSCs), which are typically the only blood cells capable of long-term self-renewal. Acute myeloid leukemia (AML) is initiated by aberrantly self-renewing malignant stem cells termed leukemia stem cells (LSCs). HSCs exhibit and depend on low levels of protein synthesis to self-renew. However, the mechanisms by which HSCs regulate protein synthesis to maintain their capacity for self-renewal in the setting of proliferative stress and leukemogenesis remain unknown. Here we show CD99, a cell surface protein upregulated in LSCs, is required for self-renewal of proliferating HSCs and LSCs. We found that loss of CD99 in HSCs and LSCs leads to increased protein synthesis and that their self-renewal capacity can be restored by translation inhibition. These data demonstrate a functional role for CD99 in constraining protein synthesis, which may promote the clonal expansion of HSCs and LSCs that leads to AML. Furthermore, they show that similar to HSCs, LSCs depend on regulated protein synthesis.

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Section: Resultsmentioning

confidence: 99%

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis

Huang

Kapti

et al. 2023

Preprint

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“…NADPH oxidase NOX2 is mainly expressed in myeloid cells, and the gp91 subunit of NADPH oxidase holoenzyme has been deleted in the CGD mice, leading to the defect in ROS production (13). While representing an escape mechanism for immune surveillance in cancer, MDSCs have a bene cial role in transplantation and function by suppressing alloreactive-T cell responses, reducing the occurrence of typical acute GVHD (aGVHD) (9,(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Because allo-reactive T cells are massively activated and proliferate during hyperacute GVHD, we ask whether these changes can be linked to the level of ROS that is produced by MDSCs (CD11b + Gr1 + ).…”

Section: Resultsmentioning

confidence: 99%

ROS Deficiency Exacerbates Donor T Cell-mediated hyperacuteGVHD And Its Predictive Value in Allogeneic HSCT in Human Patients.

Cao

Wang

Jiang

et al. 2022

Preprint

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Background: Hyperacute graft-versus-host disease (GVHD) as a severe and lethal disorder frequently occurs within 2 weeks followed by allogeneic haematopoietic stem-cell transplantation (allo-HSCT). Molecular mechanisms underlying allo-HSCT triggered hyperacute GVHD remain elusive. Method: Using a genetic NADPH-oxidase deficient CGD murine hyperacute GVHD model, we measured the proportion and related function of donor-derived T cells and recipient-derived myeloid derived suppressor cells(MDSC) by flow cytometry. Reactive oxygen species(ROS), a key molecule of immunosuppressive function, was evaluated by luminometer in murine model and cohort patients who received allo-HSCT with or without hyperacute GVHD. We also performed related interventions such as MDSC depletion and ROS agonist to discern the clinical significance of MDSC-NADPH-ROS axis on immune homeostasis. The underlying mechanism on the process of hyperacute GVHD was determined by RNA-sequence assay and cytokine profiling. Results: Here we surprisedly found that MDSC derived ROS potently prevents hyperacute GVHD by suppressing T cells activation. Moreover, in CGD mice receiving transplantation, the donor derived T cells triggered an immense allo-reactive T cell response and gained killing capacity during hyperacute GVHD. MDSCs, a main cell type for ROS production, exhibited defective suppressive effects on CD8+ and CD4+ T cells. Similarly, pharmacological depletion of MDSCs by an anti-Gr1antibody reproduced the hyperacute GVHD phenotype as seen in CGD mice. Conversely, a gain-of-function approach using a ROS agonist prevented development of hyperacute GVHD. Transcriptional analysis showed that T-cell dysregulation during hyperacute GVHD. In a cohort of 17 patients who received allo-HSCT, ROS levels were reversely correlated with hyperacute GVHD development. Together, our data provide novel mechanistic insights into the MDSC-NADPH-ROS suppressive functions in development of allo-HSCT.Conclusion: On the basis of these findings, we propose a new therapeutic paradigm by delivery of ROS agonists for effective prevention and treatment of hyperacute GVHD.

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“…Thus, the EGTC database is widely accessible to the scientific community, and all EGTC mouse lines can be obtained from the CARD R-BASE resource in Kumamoto University upon request. More than 50 groups have used EGTC mouse lines, and some of their research results have been published (Hoshii et al 2007;Vanhoutteghem et al 2009;Yamashita et al 2009;Ito et al 2010;Kim et al 2011a,b;Park et al 2012;Cid et al 2013;Kappei et al 2013;Nakahara et al 2013). In these papers, the phenotypes of the following mouse lines were analyzed: Ayu21-18 (trapped gene; Bnc2), Ayu21-81 (Kcnk5/TASK-2), Ayu21-127 (Lgr4), Ayu21-T2 (Msi2), Ayu21-T93 (Ccdc55/NSrp70), Ayu21-T346 (Hmbox1/ Hot1), Ayu21-W34 (Cadm1/Igsf4), and Ayu21-B6T44 (Cd99).…”

Section: Discussionmentioning

confidence: 99%

Database for exchangeable gene trap clones: Pathway and gene ontology analysis of exchangeable gene trap clone mouse lines

et al. 2014

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Gene trapping in embryonic stem (ES) cells is a proven method for large-scale random insertional mutagenesis in the mouse genome. We have established an exchangeable gene trap system, in which a reporter gene can be exchanged for any other DNA of interest through Cre/mutant lox-mediated recombination. We isolated trap clones, analyzed trapped genes, and constructed the database for Exchangeable Gene Trap Clones (EGTC) [http://egtc.jp]. The number of registered ES cell lines was 1162 on 31 August 2013. We also established 454 mouse lines from trap ES clones and deposited them in the mouse embryo bank at the Center for Animal Resources and Development, Kumamoto University, Japan. The EGTC database is the most extensive academic resource for gene-trap mouse lines. Because we used a promoter-trap strategy, all trapped genes were expressed in ES cells. To understand the general characteristics of the trapped genes in the EGTC library, we used Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway analysis and found that the EGTC ES clones covered a broad range of pathways. We also used Gene Ontology (GO) classification data provided by Mouse Genome Informatics (MGI) to compare the functional distribution of genes in each GO term between trapped genes in the EGTC mouse lines and total genes annotated in MGI. We found the functional distributions for the trapped genes in the EGTC mouse lines and for the RefSeq genes for the whole mouse genome were similar, indicating that the EGTC mouse lines had trapped a wide range of mouse genes.

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CD99-Dependent Expansion of Myeloid-Derived Suppressor Cells and Attenuation of Graft-Versus-Host Disease

Cited by 6 publications

References 34 publications

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis

CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis

ROS Deficiency Exacerbates Donor T Cell-mediated hyperacuteGVHD And Its Predictive Value in Allogeneic HSCT in Human Patients.

Database for exchangeable gene trap clones: Pathway and gene ontology analysis of exchangeable gene trap clone mouse lines

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