Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance
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ABSTRACT:
PROVIDER: PRJNA701667 | ENA |
REPOSITORIES: ENA
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Project description:Adoptive transfer of regulatory T cells (Tregs) has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrated an innovative approach to engineer an orthogonal IL-2-IL-2 receptor (IL-2R) pair that selectively interacts with each other and transmits native IL-2 signals, but does not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed hematopoietic chimerism model, orthogonal IL-2 injection significantly promoted orthogonal IL-2R+Foxp3GFP+CD4+ cell proliferation without increasing other T cell subsets, and facilitated donor hematopoietic cell engraftment followed by acceptance of heart allografts. Our data indicate that selective IL-2 stimulation enabled by cytokine receptor engineering improves Treg potential for the induction of organ transplantation tolerance.
2021-04-01 | GSE166713 | GEO
Project description:Adoptive transfer of Tregs has been shown to improve alloengraftment in animal models. However, it is technically challenging to expand Tregs ex vivo for the purpose of infusing large numbers of cells in the clinic. We demonstrate an innovative approach to engineering an orthogonal IL-2/IL-2 receptor (IL-2R) pair, the parts of which selectively interact with each other, transmitting native IL-2 signals, but do not interact with the natural IL-2 or IL-2R counterparts, thereby enabling selective stimulation of target cells in vivo. Here, we introduced this orthogonal IL-2R into Tregs. Upon adoptive transfer in a murine mixed hematopoietic chimerism model, orthogonal IL-2 injection significantly promoted orthogonal IL-2R+Foxp3GFP+CD4+ cell proliferation without increasing other T cell subsets and facilitated donor hematopoietic cell engraftment followed by acceptance of heart allografts. Our data indicate that selective target cell stimulation enabled by the engineered orthogonal cytokine receptor improves Treg potential for the induction of organ transplantation tolerance.
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Project description:Whereas absence of interleukin 7 (IL-7) signaling completely abrogates T and B lymphopoiesis in mice, severe combined immunodeficiency patients with mutations in the IL-7 receptor α chain still generate peripheral blood B cells. Consequently, human B lymphopoiesis has been thought to be independent of IL-7 signaling. Using flow cytometric analysis and single-cell RNA sequencing of bone marrow samples of IL-7 receptor α chain-deficient patients and healthy controls in combination with in vitro modeling of human B-cell differentiation, we demonstrate that IL-7 receptor signaling has a crucial role in human B lymphopoiesis. IL-7 drives proliferation and expansion of early B-cell progenitors, but not of pre-BII large cells. In addition, IL-7 has a limited role in the prevention of cell death. Furthermore, IL-7 guides cell fate decisions by enhancing the expression of BACH2, EBF1, and PAX5, which jointly orchestrate specification and commitment of early B-cell progenitors. In line with this observation, early B-cell progenitors of IL-7Rα-deficient patients still expressed myeloid-specific genes. Collectively, our results unveil a thus-far unknown role for IL-7 signaling in promoting the B-lymphoid fate and expanding early human B-cell progenitors, while defining important differences between mice and humans. Our results have implications for hematopoietic stem cell transplantation strategies in patients with T- B+ severe combined immunodeficiency and provide insights into the role of IL-7 receptor signaling in leukemogenesis.
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Project description:Inflammation causes increased signaling and proliferation in hematopoietic stem and progenitor cells (HSPCs), but the specific role of anti-inflammatory cytokines such as IL-10 on HSPCs is less clear. Using IL-10 receptor (IL-10R)-deficient mice we observed an increased frequency and number of HSPCs in the bone marrow (BM) relative to wild-type (WT) mice with an increased frequency of mature myeloid cells. Consistent with this, we observed reduced expansion of WT lineage-negative HSPCs after in vitro exposure to IL-10 with a specifically pronounced suppression of MPP2 cells. This reduced expansion was not observed with IL-22 or IFN-λ2, cytokines which signal through receptors that also contain the IL-10 receptor common β chain or with HSPCs from Il10ra-/- mice. To understand the mechanism of reduced expansion of MPP2 cells and preserved HSC numbers in mice with intact IL-10 signaling, we stimulated FACS-purified WT cells with IL-10 and performed expression analysis. IL-10 stimulation of HSCs increased the non-canonical Wnt pathway gene Wnt4 which is implicated in HSC quiescence and long-term function. In contrast, IL-10 stimulation in MPP2 cells modulated the TGFβ pathway and increased the expression of E2f5, a transcription factor that negatively regulates proliferation. Taken together, this study reveals a previously unrecognized role for IL-10 in suppressing HSPC cell expansion and promoting HSC function.
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Project description:Graft-versus-Host Disease (GvH) is the excessive inflammatory response by mature T cells contained in the graft during bone marrow transplantation. The allogeneic T cells recognize self-antigens as foreign and systemically attack multiple organs mostly with epithelial structures such as the skin, liver and gastrointestinal tract. We could show that IL-33 administration during allogeneic hematopoietic cell transplantation (alloHCT) increased regulatory T cell (Treg) numbers and ameliorated the outcome of GvHD. Furthermore, it is known that IL-33 also has an impact on myeloid cell compartments and we showed that IL-33 delivery together with a loss of FoxP3 positive Treg led to a massive expansion of myeloid cells. With the underlying experiment we wanted to further characterize the myeloid cells when Treg are lost, therefore mice were treated with IL-33 and one group had a loss in FoxP3 cells. CD11b+F4/80+Gr-1lo myeloid cells were sorted and analyzed in the microarray. The examined myeloid cell population shows strong activation of the IFNg transcriptome and are prone to M1 macrophage polarization. Therefore, Treg restrain myeloid cell expansion and polarization during IL-33 delivery.
2016-06-27 | E-MTAB-4677 | biostudies-arrayexpress
Project description:IL-7-dependent STAT1 activation limits homeostatic CD4+ T cell expansion
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Project description:Adoptive T cell therapy (ATT) requires activation, expansion and, for certain indications, gene-modification of T cells. Sufficient numbers of T cells and the characteristics of the final T cell product decisively determine the success of treatment. In this study, we addressed the question if prolonged expansion by simply using the cytokine combination IL-7/IL-15 could enhance the T cell yield without sacrifying T cell functionality. Prolonged expansion resulted in a 50-fold increase of CD8+ central memory T cells (Tcm). RNA sequencing and differential analysis of short-term expanded (ST) and long-term expanded (LT) murine CD8+ and CD4+ Tcm revealed that LT T cells retain a gene expression profile related to Tcm/stem central memory T cells (Tscm). Upon anti-CD3/CD28 stimulation, ST and LT T cells proliferated and underwent apoptosis comparably. IL-2 and INF- production was higher for LT T cells. Engraftment, persistence and anti-tumor capacities of LT murine T cells were preserved after in vivo administration. We confirmed our in vitro findings for human T cells. Our study demonstrates the feasibility of manufacturing an increased number of favorable T cells with Tcm/Tscm properties for ATT by a prolonged, minimally manipulative expansion protocol using the cytokines IL-7 and IL-15.
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Project description:Restoration of hematopoiesis upon bone marrow (BM) transplantation relies on the engraftment, expansion and function of transplanted hematopoietic stem cells (HSC). However, the number of donorâderived HSC typically remain much below that present in normal individuals and this likely limits and delays hematopoietic recovery. HSC depend on supportive stromal niches, however, whether the preâconditioning required for BM transplantation damages this stromal niche has not been evaluated extensively. Using mouse models, we now find that that BM stroma cells (BMSC) are severely and permanently damaged by preâconditioning. Transplantation of primary but not cultured BMSC quantitatively reconstitutes stroma function in vivo, which is mediated by a multipotent CD73+ CD105â Sca1+ BMSC subpopulation. BMSC coâtransplantation significantly ameliorates clinical side effects of BM transplantation and doubles expansion of functional, donorâ derived HSC, demonstrating the potential of stroma transplantation to improve HSC transplantation. Purified CD45âTer119âCD73+ CD105â and CD45âTer119âCD73+ CD105+ cells were directly sorted on lysis buffer with FACS Aria 2 in triplicate.
2016-09-01 | E-GEOD-79091 | biostudies-arrayexpress