Interleukin-1? Induces Human Endothelial Surface Expression and Trans-presentation of Interleukin-15 by Relieving let-7c-3p Suppression of Protein Translation
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE266374 | GEO | 2024/09/30
REPOSITORIES: GEO
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Project description:Expression of interleukin-15 (IL-15) on the surface of human graft endothelial cells (ECs) bound to the IL-15 receptor a (IL-15Ra) subunit can increase the activation of cytotoxic T lymphocytes (CTLs), potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1b synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-kB. Here we report that cultured human ECs express 8 differently spliced IL-15 transcripts. Remarkably, IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA Polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1β causes an NF-kB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p antimir can induce EC surface expression of IL-15/IL-15Ra in the absence of complement activation or of IL-1, enabling IL-15 trans-presentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for trans-presentation.
2024-09-30 | GSE266373 | GEO
Project description:Expression of interleukin-15 (IL-15) on the surface of human graft endothelial cells (ECs) bound to the IL-15 receptor a (IL-15Ra) subunit can increase the activation of cytotoxic T lymphocytes (CTLs), potentiating allograft rejection. Our previous work showed that surface expression of this protein complex could be induced by alloantibody-mediated complement activation through increased IL-1b synthesis, secretion, and autocrine/paracrine IL-1-mediated activation of NF-kB. Here we report that cultured human ECs express 8 differently spliced IL-15 transcripts. Remarkably, IL-1β does not alter the expression level of any IL-15 transcript but induces surface expression independently of RNA Polymerase II-mediated transcription while requiring new protein translation. Mechanistically, IL-1β causes an NF-kB-mediated reduction in the level of microRNA Let-7c-3p, thereby relieving a block of translation of IL-15 surface protein. Let7c-3p antimir can induce EC surface expression of IL-15/IL-15Ra in the absence of complement activation or of IL-1, enabling IL-15 trans-presentation to boost CD8 T cell activation. Because of the complexity we have uncovered in IL-15 regulation, we recommend caution in interpreting increased total IL-15 mRNA or protein levels as a surrogate for trans-presentation.
2024-09-30 | GSE266372 | GEO
Project description:Interleukin-1? Induces Human Endothelial Surface Expression and Trans-presentation of Interleukin-15 by Relieving let-7c-3p Suppression of Protein Translation
| PRJNA1106839 | ENA
Project description:Interleukin-1ßces Human Endothelial Surface Expression and Trans-presentation of Interleukin-15 by Relieving let-7c-3p Suppression of Protein Translation (small RNA-Seq)
| PRJNA1106843 | ENA
Project description:Interleukin-1β Induces Human Endothelial Surface Expression and Trans-presentation of Interleukin-15 by Relieving let-7c-3p Suppression of Protein Translation (bulk RNA-Seq)
| PRJNA1106841 | ENA
Project description:Interleukin-15 (IL-15) is essential for the survival of memory CD8(+) and CD4(+) T cell subsets, and natural killer and natural killer T cells. Here, we describe a hitherto unreported role of IL-15 in regulating homoeostasis of naive CD4(+) T cells. Adoptive transfer of splenocytes from non-obese diabetic (NOD) mice results in increased homeostatic expansion of T cells in lymphopenic NOD.scid.Il15(-/-) mice when compared to NOD.scid recipients. The increased accumulation of CD4(+) T cells is also observed in NOD.Il15(-/-) mice, indicating that IL-15-dependent regulation also occurs in the absence of lymphopenia. NOD.scid mice lacking the IL-15Rα chain, but not those lacking the common gamma chain, also show increased accumulation of CD4(+) T cells. These findings indicate that the IL-15-mediated regulation occurs directly on CD4(+) T cells and requires trans-presentation of IL-15. CD4(+) T cells expanding in the absence of IL-15 signaling do not acquire the characteristics of classical regulatory T cells. Rather, CD4(+) T cells expanding in the absence of IL-15 show impaired antigen-induced activation and IFN-γ production. Based on these findings, we propose that the IL-15-dependent regulation of the naive CD4(+) T-cell compartment may represent an additional layer of control to thwart potentially autoreactive cells that escape central tolerance, while permitting the expansion of memory T cells.
| S-EPMC4085515 | biostudies-other
Project description:IL-15 plays a pivotal role in the long-term survival of T cells and immunological memory. Its receptor consists of three subunits (IL-15Rα, IL-2/15Rβ, and γc). IL-15 functions mainly via trans-presentation (TP), during which an APC expressing IL-15 bound to IL-15Rα presents the ligand to the βγc receptor-heterodimer on a neighboring T/NK cell. To date, no direct biophysical evidence for the intercellular assembly of the IL-15R heterotrimer exists. Ag presentation (AP), the initial step of T cell activation, is also based on APC-T cell interaction. We were compelled to ask whether AP has any effect on IL-15 TP or whether they are independent processes. In our human Raji B cell-Jurkat T cell model system, we monitored inter-/intracellular protein interactions upon formation of IL-15 TP and AP receptor complexes by Förster resonance energy transfer measurements. We detected enrichment of IL-15Rα and IL-2/15Rβ at the synapse and positive Förster resonance energy transfer efficiency if Raji cells were pretreated with IL-15, giving direct biophysical evidence for IL-15 TP. IL-15Rα and MHC class II interacted and translocated jointly to the immunological synapse when either ligand was present, whereas IL-2/15Rβ and CD3 moved independently of each other. IL-15 TP initiated STAT5 phosphorylation in Jurkat cells, which was not further enhanced by AP. Conversely, IL-15 treatment slightly attenuated Ag-induced phosphorylation of the CD3ζ chain. Our studies prove that in our model system, IL-15 TP and AP can occur independently, and although AP enhances IL-15R assembly, it has no significant effect on IL-15 signaling during TP. Thus, IL-15 TP can be considered an autonomous, Ag-independent process.
| S-EPMC8578424 | biostudies-literature
Project description:Natural killer (NK) cells are important effector cells in the control of infections. The cellular and molecular signals required for NK cell activation in vivo remain poorly defined. By using a mouse model for the inducible ablation of dendritic cells (DCs), we showed that the in vivo priming of NK cell responses to viral and bacterial pathogens required the presence of CD11c(high) DCs. After peripheral Toll-like receptor (TLR) stimulation, NK cells were recruited to local lymph nodes, and their interaction with DCs resulted in the emergence of effector NK cells in the periphery. NK cell priming was dependent on the recognition of type I IFN signals by DCs and the subsequent production and trans-presentation of IL-15 by DCs to resting NK cells. CD11c(high) DC-derived IL-15 was necessary and sufficient for the priming of NK cells. Our data define a unique in vivo role of DCs for the priming of NK cells, revealing a striking and previously unappreciated homology to T lymphocytes of the adaptive immune system.
| S-EPMC2084390 | biostudies-literature
Project description:The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self-major histocompatibility complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2(-/-)gamma c(-/-) mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor alpha (IL-15R alpha) significantly augmented human NK cells. IL-15-IL-15R alpha complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16(+)KIR(+) NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56(hi)CD16(-)KIR(-) to CD56(lo)CD16(+)KIR(-), and finally to CD56(lo)CD16(+)KIR(+). These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15-responsive cells during immunotherapy strategies.
| S-EPMC2626663 | biostudies-literature
Project description:IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.
| S-EPMC8092395 | biostudies-literature