Similar Datasets
Project description:Trained immunity refers to epigenetic and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to a heightened response to secondary stimuli. Although this innate immune memory contributes to host defense against infections, it can also have maladaptive consequences in a broad range of immune-driven conditions. During the past decade, we have gained an increasingly better understanding of the molecular regulation of trained immunity, but the role of adaptive immune cells in modulation of trained immunity remains largely unknown. Here, we show that T cell interactions contribute to the induction of trained immunity in monocytes and that this mediated by CD40-TRAF6 signaling. Specifically, we found that inhibiting CD40-TRAF6 signaling prevents the induction of functional, transcriptomic, metabolic and epigenetic changes associated with trained immunity. Apart from detailed in vitro studies, we inhibited CD40-TRAF6 signaling in vivo in myeloid cells in a murine heart transplantation model which resulted in prolonged allograft survival. When the animals were additionally treated with costimulatory blockade by CTLA4-Ig, we observed immunological tolerance to the graft. Combined, our study reveals that trained immunity induction is regulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells, and that this signaling can be efficiently leveraged for therapeutic purposes.
2024-08-26 | GSE228183 | GEO
Project description:Trained immunity refers to epigenetic and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to a heightened response to secondary stimuli. Although this innate immune memory contributes to host defense against infections, it can also have maladaptive consequences in a broad range of immune-driven conditions. During the past decade, we have gained an increasingly better understanding of the molecular regulation of trained immunity, but the role of adaptive immune cells in modulation of trained immunity remains largely unknown. Here, we show that T cell interactions contribute to the induction of trained immunity in monocytes and that this mediated by CD40-TRAF6 signaling. Specifically, we found that inhibiting CD40-TRAF6 signaling prevents the induction of functional, transcriptomic, metabolic and epigenetic changes associated with trained immunity. Apart from detailed in vitro studies, we inhibited CD40-TRAF6 signaling in vivo in myeloid cells in a murine heart transplantation model which resulted in prolonged allograft survival. When the animals were additionally treated with costimulatory blockade by CTLA4-Ig, we observed immunological tolerance to the graft. Combined, our study reveals that trained immunity induction is regulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells, and that this signaling can be efficiently leveraged for therapeutic purposes.
2024-08-26 | GSE228182 | GEO
Project description:Trained immunity is characterized by histone modifications and metabolic changes in innate immune cells following exposure to inflammatory signals, leading to heightened responsiveness to secondary stimuli. Although our understanding of the molecular regulation of trained immunity has increased, the role of adaptive immune cells herein remains largely unknown. Here, we show that T cells modulate trained immunity via cluster of differentiation 40-tissue necrosis factor receptor-associated factor 6 (CD40-TRAF6) signaling. CD40-TRAF6 inhibition modulates functional, transcriptomic, and metabolic reprogramming and modifies histone 3 lysine 4 trimethylation associated with trained immunity. Besides in vitro studies, we reveal that single-nucleotide polymorphisms in the proximity of CD40 are linked to trained immunity responses in vivo and that combining CD40-TRAF6 inhibition with cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig)-mediated co-stimulatory blockade induces long-term graft acceptance in a murine heart transplantation model. Combined, our results reveal that trained immunity is modulated by CD40-TRAF6 signaling between myeloid and adaptive immune cells and that this can be leveraged for therapeutic purposes.
| S-EPMC11536040 | biostudies-literature
Project description:Trained immunity is facilitated by T cell-induced CD40-TRAF6 signaling
| PRJNA948444 | ENA
Project description:Trained immunity is facilitated by T cell-induced CD40-TRAF6 signaling [RNA-seq]
| PRJNA948447 | ENA
Project description:Trained immunity is facilitated by T cell-induced CD40-TRAF6 signaling [ChIP-seq]
| PRJNA948446 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-04-27 | GSE180032 | GEO
Project description:BackgroundDisrupting the costimulatory CD40-CD40L dyad reduces atherosclerosis, but can result in immune suppression. The authors recently identified small molecule inhibitors that block the interaction between CD40 and tumor necrosis factor receptor-associated factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity.ObjectivesThis study evaluates the potential of TRAF-STOP treatment in atherosclerosis.MethodsThe effects of TRAF-STOPs on atherosclerosis were investigated in apolipoprotein E deficient (Apoe-/-) mice. Recombinant high-density lipoprotein (rHDL) nanoparticles were used to target TRAF-STOPs to macrophages.ResultsTRAF-STOP treatment of young Apoe-/- mice reduced atherosclerosis by reducing CD40 and integrin expression in classical monocytes, thereby hampering monocyte recruitment. When Apoe-/- mice with established atherosclerosis were treated with TRAF-STOPs, plaque progression was halted, and plaques contained an increase in collagen, developed small necrotic cores, and contained only a few immune cells. TRAF-STOP treatment did not impair "classical" immune pathways of CD40, including T-cell proliferation and costimulation, Ig isotype switching, or germinal center formation, but reduced CD40 and β2-integrin expression in inflammatory monocytes. In vitro testing and transcriptional profiling showed that TRAF-STOPs are effective in reducing macrophage migration and activation, which could be attributed to reduced phosphorylation of signaling intermediates of the canonical NF-κB pathway. To target TRAF-STOPs specifically to macrophages, TRAF-STOP 6877002 was incorporated into rHDL nanoparticles. Six weeks of rHDL-6877002 treatment attenuated the initiation of atherosclerosis in Apoe-/- mice.ConclusionsTRAF-STOPs can overcome the current limitations of long-term CD40 inhibition in atherosclerosis and have the potential to become a future therapeutic for atherosclerosis.
| S-EPMC5800892 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-30 | GSE190530 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-07-18 | GSE184684 | GEO