IL-34 actions on FOXP3+ Tregs and CD14+ monocytes control human graft rejection
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE151194 | GEO | 2020/05/27
REPOSITORIES: GEO
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Project description:IL-34 actions on FOXP3+ Tregs and CD14+ monocytes control human graft rejection
| PRJNA635103 | ENA
Project description:Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4+ and CD8+ FOXP3+ Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4+ and CD8+ FOXP3+ Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graft-vs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4+ and CD8+ FOXP3+ Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8+ Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3+ Tregs.
| S-EPMC7431608 | biostudies-literature
Project description:IL-34-differenciated CD14+CD115+ monocytes expand and potentiate IL-34+ Tregs to control human transplant rejection
| PRJEB37095 | ENA
Project description:Tregs play a pivotal role in inducing and maintaining donor-specific transplant tolerance. The T cell immunoglobulin and mucin domain-3 protein (TIM-3) is expressed on many fully activated effector T cells. Along with program death 1 (PD-1), TIM-3 is used as a marker for exhausted effector T cells, and interaction with its ligand, galectin-9, leads to selective death of TIM-3+ cells. We report herein the presence of a galectin-9-sensitive CD4+FoxP3+TIM-3+ population of T cells, which arose from CD4+FoxP3+TIM-3- proliferating T cells in vitro and in vivo and were often PD-1+. These cells became very prominent among graft-infiltrating Tregs during allograft response. The frequency and number of TIM-3+ Tregs peaked at the time of graft rejection and declined thereafter. Moreover, these cells also arise in a tolerance-promoting donor-specific transfusion model, representing a pool of proliferating, donor-specific Tregs. Compared with TIM-3- Tregs, TIM-3+ Tregs, which are often PD-1+ as well, exhibited higher in vitro effector function and more robust expression of CD25, CD39, CD73, CTLA-4, IL-10, and TGF-β but not galectin-9. However, these TIM-3+ Tregs did not flourish when passively transferred to newly transplanted hosts. These data suggest that a heretofore unrecognized graft-infiltrating, short-lived subset of Tregs can restrain rejection.
| S-EPMC3386804 | biostudies-literature
Project description:IL-34 deficiency impairs FOXP3+ Treg function and increases susceptibility to diseases
| PRJEB52489 | ENA
Project description:BATF3 has been shown to inhibit FOXP3 expression in differentiating CD4 T cells, however, the role of IRF4 in this inhibition is unexplored. IRF4 binds DNA weakly on its own and requires interactions with other transcription factors. We investigated how BATF3/IRF4 interactions are necessary for IRF4 binding and BATF3-mediated FOXP3 inhibition.
2022-08-16 | GSE211182 | GEO
Project description:Gastrointestinal (GI) tract graft versus host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT) and is attributable to dysregulation that occurs between the effector and regulatory arms of the immune system. Whereas regulatory T cells have a primary role in counterbalancing GVHD-induced inflammation, identifying and harnessing other pathways that promote immune tolerance remains a major goal in this disease. Herein, we have identified interleukin 34 (IL-34) as a tissue-intrinsic regulatory cytokine that is able to mitigate the severity of GVHD within the GI tract. Specifically, we observed that absence of recipient IL-34 production exacerbated GVHD lethality, promoted intestinal epithelial cell death, and compromised barrier integrity. Mechanistically, the absence of host IL-34 skewed donor macrophages towards a proinflammatory phenotype and augmented the accumulation of pathogenic CD4+ GM-CSF+ T cells within the colon. Conversely, the administration of recombinant IL-34 significantly reduced GVHD mortality and inflammation in the GI tract which was dependent upon the expression of apolipoprotein E (ApoE) in donor macrophages. Complementary genetic and imaging approaches demonstrated that intestinal epithelial cells were the biologically relevant source of IL-34. Colonic biopsies from patients with GVHD also revealed expression of IL-34 in intestinal epithelial cells, as well as ApoE in lamina propria macrophages, validating similar cellular localization in humans. Thus, these studies define IL-34 as an intestinal epithelial-derived cytokine that regulates macrophage polarization in an ApoE-dependent manner, positioning this cytokine as a key regulator of GVHD in the GI tract and a potential therapeutic target for amelioration of this disease.
2025-07-09 | GSE252891 | GEO
Project description:Treg cell therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but its use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knock-in in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we target the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-ablated Tregs upregulate cytokine expression, effects on suppressive capacity in vitro manifest slowly and primarily in memory Tregs. Moreover, FOXP3-ablated Tregs retain their characteristic protein, transcriptional, and DNA methylation profile. Instead, FOXP3 maintains DNA methylation at regions enriched for AP-1 binding sites. Thus, while FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knock-in with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies.
2021-08-03 | GSE176191 | GEO
Project description:Burkholderia thailandensis 34 strain:34 Genome sequencing
| PRJNA178704 | ENA
Project description:Objectives. Immune homeostasis in the intestinal tract is tightly controlled by FOXP3+ regulatory T cells (Tregs), with loss of this Treg-mediated control linked to development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites strengthen intestinal Treg activity, leading to the notion that parasite-derived products could be harnessed and used as an immunoregulatory therapy for IBD. It has been previously demonstrated that the parasite Heligmosomoides polygyrus secretes a molecule (Hp-TGM) which mimics the ability of TGF-β to induce FOXP3 expression in CD4+ T cells. Our aim was to investigate whether Hp-TGM could induce human FOXP3+ Tregs as a potential therapeutic approach. Methods. Human CD4+ T cells from healthy volunteers were expanded in the presence of Hp-TGM or mammalian TGF-β. The induction of Tregs was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CTLA-4 and CD25. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was assessed by cellular co-culture suppression assays and secreted cytokines measured by cytometric bead array. Results. Hp-TGM efficiently induced FOXP3 expression (>60%), in addition to another Treg functional marker CTLA-4. Hp-TGM caused epigenetic modification of the FOXP3 loci to a greater extent than did TGF-β. Hp-TGM-induced Tregs also had superior suppressive function compared to TGF--induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Hp-TGM also induced a Treg phenotype in in vivo differentiated Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. Conclusion. These data indicate Hp-TGM has the potential to be used to generate stable human FOXP3+ Tregs to treat IBD.
2021-04-29 | GSE164548 | GEO