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      CD71 +VISTA + erythroid cells promote the development and function of regulatory T cells through TGF-β

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          Abstract

          Cell-surface transferrin receptor (CD71 +) erythroid cells are abundant in newborns with immunomodulatory properties. Here, we show that neonatal CD71 + erythroid cells express significant levels of V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) and, via constitutive production of transforming growth factor (TGF)- β, play a pivotal role in promotion of naïve CD4 + T cells into regulatory T cells (Tregs). Interestingly, we discovered that CD71 +VISTA + erythroid cells produce significantly higher levels of TGF-β compared to CD71 +VISTA erythroid cells and CD71 + erythroid cells from the VISTA knock-out (KO) mice. As a result, CD71 +VISTA + erythroid cells—compared to CD71 +VISTA and CD71 + erythroid cells from the VISTA KO mice—significantly exceed promotion of naïve CD4 + T cells into induced Tregs (iTreg) via TGF-β in vitro. However, depletion of CD71 + erythroid cells had no significant effects on the frequency of Tregs in vivo. Surprisingly, we observed that the remaining and/or newly generated CD71 + erythroid cells following anti-CD71 antibody administration exhibit a different gene expression profile, evidenced by the up-regulation of VISTA, TGF-β1, TGF-β2, and program death ligand-1 (PDL-1), which may account as a compensatory mechanism for the maintenance of Treg population. We also observed that iTreg development by CD71 + erythroid cells is mediated through the inhibition of key signaling molecules phosphorylated protein kinase B (phospho-Akt) and phosphorylated mechanistic target of rapamycin (phospho-mTOR). Finally, we found that elimination of Tregs using forkhead box P3 (FOXP3)-diptheria toxin receptor (DTR) mice resulted in a significant expansion in the frequency of CD71 + erythroid cells in vivo. Collectively, these studies provide a novel, to our knowledge, insight into the cross-talk between CD71 + erythroid cells and Tregs in newborns. Our results highlight the biological role of CD71 + erythroid cells in the neonatal period and possibly beyond.

          Author summary

          The primary role of the red blood cells is to transport oxygen, but we know relatively little about the other functions they perform. Following maturation, red blood cells exit the bone marrow and enter blood circulation. Their immature counterparts are normally absent or in very low frequency in the blood of healthy adults. However, we showed previously that immature red blood cells are abundant in the spleens of neonatal mice and in human umbilical cord blood and that these cells possess immunological properties. In this report, we studied a subset of neonatal immature red blood cells that express a protein called V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) on their surface. We found that the presence of VISTA enables the cells to repeatedly produce the regulatory cytokine TGF-β. TGF-β induces a subset of naïve lymphocytes—the CD4 + T cells—and converts them into regulatory T cells, also known as Tregs. Tregs modulate and suppress other immune cells. Our studies provide novel insights, to our knowledge, into the immunological role of immature red blood cells in newborns.

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          Most cited references 34

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          Roles of TGF-beta family signaling in stem cell renewal and differentiation.

          Transforming growth factor (TGF)-betas and their family members, including bone morphogenetic proteins (BMPs), Nodal and activins, have been implicated in the development and maintenance of various organs, in which stem cells play important roles. Stem cells are characterized by their ability to self-renew and to generate differentiated cells of a particular tissue, and are classified into embryonic and somatic stem cells. Embryonic stem (ES) cells self-renew indefinitely and contribute to derivatives of all three primary germ layers. In contrast, somatic stem cells, which can be identified in various adult organs, exhibit limited abilities for self-renewal and differentiation in most cases. The multi-lineage differentiation capacity of ES cells and somatic stem cells has opened possibilities for cell replacement therapies for genetic, malignant and degenerative diseases. In order to utilize stem cells for therapeutic applications, it is essential to understand the extrinsic and intrinsic factors regulating self-renewal and differentiation of stem cells. More recently, induced pluripotent stem (iPS) cells have been generated from mouse and human fibroblasts that resemble ES cells via ectopic expression of four transcription factors. iPS cells may have an advantage in regenerative medicine, since they overcome the immunogenicity and ethical controversy of ES cells. Moreover, recent studies have highlighted the involvement of cancer stem cells during the formation and progression of various types of cancers, including leukemia, glioma, and breast cancer. Here, we illustrate the roles of TGF-beta family members in the maintenance and differentiation of ES cells, somatic stem cells, and cancer stem cells.
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            VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy.

            In the past few years, the field of cancer immunotherapy has made great progress and is finally starting to change the way cancer is treated. We are now learning that multiple negative checkpoint regulators (NCR) restrict the ability of T-cell responses to effectively attack tumors. Releasing these brakes through antibody blockade, first with anti-CTLA4 and now followed by anti-PD1 and anti-PDL1, has emerged as an exciting strategy for cancer treatment. More recently, a new NCR has surfaced called V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation (VISTA). This NCR is predominantly expressed on hematopoietic cells, and in multiple murine cancer models is found at particularly high levels on myeloid cells that infiltrated the tumors. Preclinical studies with VISTA blockade have shown promising improvement in antitumor T-cell responses, leading to impeded tumor growth and improved survival. Clinical trials support combined anti-PD1 and anti-CTLA4 as safe and effective against late-stage melanoma. In the future, treatment may involve combination therapy to target the multiple cell types and stages at which NCRs, including VISTA, act during adaptive immune responses.
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              Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells.

              The β-galactoside-binding protein galectin-9 is critical in regulating the immune response, but the mechanism by which it functions remains unclear. We have demonstrated that galectin-9 is highly expressed by induced regulatory T cells (iTreg) and was crucial for the generation and function of iTreg cells, but not natural regulatory T (nTreg) cells. Galectin-9 expression within iTreg cells was driven by the transcription factor Smad3, forming a feed-forward loop, which further promoted Foxp3 expression. Galectin-9 increased iTreg cell stability and function by directly binding to its receptor CD44, which formed a complex with transforming growth factor-β (TGF-β) receptor I (TGF-βRI), and activated Smad3. Galectin-9 signaling was further found to regulate iTreg cell induction by dominantly acting through the CNS1 region of the Foxp3 locus. Our data suggest that exogenous galectin-9, in addition to being an effector molecule for Treg cells, acts synergistically with TGF-β to enforce iTreg cell differentiation and maintenance.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draft
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Software
                Role: Methodology
                Role: Formal analysisRole: Validation
                Role: Data curationRole: Resources
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                14 December 2018
                December 2018
                14 December 2018
                : 16
                : 12
                Affiliations
                [1 ] Department of Dentistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
                [2 ] The Applied Genomics Core, Office of Research, University of Alberta, Edmonton, Canada
                [3 ] Department of Veterans Affairs Medical Center, Research Service, White River Junction, Vermont, United States of America
                [4 ] Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire, United States of America
                [5 ] Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada
                National Jewish Health, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Article
                pbio.2006649
                10.1371/journal.pbio.2006649
                6310287
                30550561
                © 2018 Shahbaz et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 7, Tables: 0, Pages: 26
                Product
                Funding
                Canadian Institutes of Health Research (CIHR) http://www.cihr-irsc.gc.ca (grant number 353953, 360929, 385988). This work was supported by a Foundation Scheme Grant from CIHR, a CIHR New Investigator Salary Award, and a CIHR New Investigator Award in Maternal, Reproductive, Child and Youth Health (received by SE). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Women and Children’s Health Research Institute (WCHRI) https://www.wchri.org. This study was also supported by an Innovation Grant from WCHRI (received by SE). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Department of Veterans Affairs Merit Review award https://www.research.va.gov/resources/policies/merit_review.cfm. This work was also supported in part by a Department of Veterans Affairs Merit Review award (received by RF). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                2018-12-28
                RNA-seq data are available from SRA database (PRJNA505315), and other relevant data are within the paper and its Supporting Information files.

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