Nanostring gene expression profiling of TurboCAR T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE206373 | GEO | 2023/08/09
REPOSITORIES: GEO
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Project description:Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γc, We find that in the IL-15/IL-15Rα/IL-2Rβ/γc quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γc identically to the IL-2/IL-2Rα/IL-2Rβ/γc complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ/γc dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15- versus IL-2-based immunotherapeutics. RNA-Seq is conducted in mouse CD8+ T cells, not treated or treated with IL2 or IL15 for indicated concentrations (1nM or 500nM) and times (4hr or 24hr).
2012-11-01 | E-GEOD-40350 | biostudies-arrayexpress
Project description:Half of the patients with high-risk neuroblastoma (NB) who receive GD2-targeted monoclonal antibody do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to interleukin (IL)2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (ICs) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 to hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against NB. We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high NB cell lines in vitro. T-cell deficient mice with orthotopic patient-derived xenografts (PDXs) and immunocompetent mice with transplantable orthotopic NB were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq). Hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic NB, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment. Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing NB.
2022-09-01 | GSE206628 | GEO
Project description:The common γ chain (γc; IL2RG) is a subunit of the interleukin (IL) receptors for the γc cytokines IL2, IL4, IL7, IL9, IL15, and IL21. Because of the lack of appropriate neutralizing antibodies recognizing IL2RG, it has been difficult to thoroughly interrogate the role of γc cytokines in inflammatory and autoimmune disease settings. To determine whether γc cytokines might be targeted for T-cell-mediated disease prevention and treatment, we generated a new γc cytokine receptor antibody, REGN7257. Biochemical, structural and in vitro analysis showed that REGN7257 binds with high affinity to IL2RG and potently blocks signaling of all γc cytokines. In nonhuman primates, REGN7257 efficiently suppressed T-cells without impacting granulocytes, platelets or red blood cells. Using REGN7257, we showed that γc cytokines drive T-cell-mediated disease in mouse models of graft-versus-host disease (GVHD) and multiple sclerosis, by impacting multiple aspects of the pathogenic response. Importantly, we discovered that our xenogeneic GVHD mouse model recapitulates hallmarks of both acute and chronic GVHD, with T-cell expansion/infiltration into tissues and liver fibrosis, as well as hallmarks of immune aplastic anemia, with bone marrow aplasia and peripheral cytopenia. And we showed that γc cytokines contribute to disease pathology by driving all of these features. Overall, by demonstrating that broad inhibition of γc cytokine signaling with REGN7257 protects from immune-mediated disorders, our data provide evidence of γc cytokines as key drivers of pathogenic T-cell responses, offering a potentially novel strategy for the management of T-cell-mediated diseases.
2022-10-04 | GSE214625 | GEO
Project description:Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γc, We find that in the IL-15/IL-15Rα/IL-2Rβ/γc quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γc identically to the IL-2/IL-2Rα/IL-2Rβ/γc complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ/γc dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15- versus IL-2-based immunotherapeutics.
2012-11-01 | GSE40350 | GEO
Project description:Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft versus host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation. Genome-wide transcription factors binding of STAT5 and mRNA-Sequencing of gene expression profiles in human pre-activated CD8+ T cells.
2015-06-16 | E-GEOD-64713 | biostudies-arrayexpress
Project description:Interleukin-2 (IL-2) is a pleiotropic cytokine that regulates lymphocyte function by signaling through heterodimerization of the IL-2Rβ and γc receptor subunits. Previously, we engineered an IL-2 “superkine” (H9) with enhanced affinity for IL-2Rβ. Here, we describe next-generation IL-2 variants that function as “receptor signaling clamps.” They retain high-affinity for IL-2Rβ, thereby inhibiting binding of endogenous IL-2, but their engagement of γc is weakened, thereby attenuating IL-2Rβ-γc heterodimerization. These IL-2 analogues act as partial agonists and can differentially affect lymphocytes poised at distinct activation thresholds. Moreover, one of these variants potently antagonized IL-2 and IL-15 signaling and function better than blocking antibodies against IL-2Rα or IL-2Rβ. Furthermore, this mutein prolonged survival in a model of graft versus host disease and blocked spontaneous proliferation of smoldering adult T-cell leukemia (ATL) T cells ex vivo. This receptor-clamping approach may be a general mechanism-based strategy for engineering cytokine partial agonists for therapeutic immunomodulation.
2015-06-16 | GSE64713 | GEO
Project description:"γc" cytokines are a family whose receptors share a “common gamma chain” signaling moiety, and play central roles in the differentiation, homeostasis and communications of all immunocyte lineages. As a resource to better understand their range and specificity of action, we profiled by RNAseq the immediate-early responses to the main γc cytokines, across all immunocyte lineages. The results show a different response landscape than expected: broader, with a strong Myc-controlled resetting of biosynthetic and metabolic pathways, a major downregulation component, and extensive overlap between cytokines (one cytokine doing in one cell what another does elsewhere). Various mechanisms appear involved: fast transcriptional activation, chromatin remodeling, and mRNA destabilization. Other surprises are uncovered: IL2 effects in mast cells, major shifts between follicular and marginal-zone B cells, paradoxical and cell-specific cross-talk between IFN and γc signaling, or an NK-T like program induced by IL21 in CD8+ T cells.
2022-07-22 | GSE208138 | GEO
Project description:The common gamma chain (γc) is required for productive signaling by interleukin (IL)-15, IL-21 and IL-2, which are critically involved in immune activation and regulation. IL-21 and IL-15 are implicated in the pathogenesis of type-1 diabetes, graft-versus-host disease, and celiac disease (CeD), a gluten-mediated autoimmune-like enteropathy. Attempts to treat type-1 diabetes and graft-versus-host disease with biologics targeting one particular cytokine have failed. Both IL-15 and IL-21 have been suggested to drive activation of cytotoxic T cells (CTL) that are the effectors mediating tissue destruction in CeD and organ-specific autoimmune disorders. We show that the concomitant upregulation of IL-15 and IL-21 occurs only in full-blown CeD with villous atrophy. BNZ-2, a peptide that targets the γc, was able to block the cooperative IL-15/IL-21 mediated transcriptional activation of human tissue-resident intraepithelial CTL. Importantly, this inhibition was specific and did not interfere with IL-2 signaling, a cytokine with known immunoregulatory functions. Moreover, BNZ-2 blocked gluten-induced IFN-γ production in small intestinal organ cultures from CeD patients. These observations identify BNZ-2 as a therapeutic candidate for immune disorders in which IL-15 and IL-21 cooperate to induce CTL-mediated tissue damage.
2018-10-06 | GSE120904 | GEO
Project description:APRIL is involved in the development of B-cell lymphomas. However, in tumors the source of APRIL is paracrine while one signaling receptor, BCMA, is intracellular, raising the question on how APRIL may signal. In fact, tumor cells internalized APRIL via their surface HSPG. Then, APRIL trafficked into endosomes to finally interact with Golgic BCMA, whose sequence harbors strong identities with sorting nexins. Intracellular APRIL/BCMA interactions activated the canonical NF-kB pathway, and mediated from tumor cells an immunosuppressive response including IL-10 upregulation. Absence of APRIL/BCMA interactions impaired tumor growth in mice, and APRIL internalization by tumor cells correlated with a reduced survival for patients. Taken together, the present study elucidates a fully intracellular signaling pathway, key to B-cell lymphoma development.
2018-04-26 | GSE113643 | GEO