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Mitochondrial Calcium Uniporter modulates CD8+ T cell stemness programs and regulates alloimmunity [RNAseq 1]

ABSTRACT: Stemness programs sustain the alloreactive CD8+ T cells pool in epithelial tissues to mediate graft-versus-host disease (GVHD). Despite suppressing T cell activation, pan Ca2+ signaling inhibition treatment retains stemness programs, and cannot prevent GVHD development in the chronic stage while enhances risks for tumor relapse and infection. Whether specific Ca2+ channels dictate T cell alloreactivity remains to be uncovered. Here we show the mitochondrial calcium uniporter (MCU) regulates stemness programs in alloreactive CD8+ T cells. Genetic ablation of Mcu impaired the transcription of stemness genes and promoted alloreactive CD8+ T cell exhaustion development. Mechanistically, Mcu deficiency increased NF-κB activity during TCR stimulation, enhanced CD25 level hence the sensitivity to IL2. After activation, Mcu expression was intrinsically tuned back to baseline level. Ectopic expression of Mcu decreased the expression of pro-survival stemness genes and enhanced restimulation-induced cell death (RICD), abrogating alloreactive CD8+ T cell GVHD-inducing capacity. Pharmacological enhancement of MCU function with the FDA approved anti-malaria drug artesunate reduced GVHD but spared anti-leukemia potency. These findings unravel MCU controls stemness programs in alloreactive CD8+ T cells, highlighting the translational potential of MCU-targeting genetic or pharmacological approaches in the modulation of T cell alloimmunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE306362 | GEO | 2026/08/31

REPOSITORIES: GEO

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Mitochondrial Calcium Uniporter modulates CD8+ T cell stemness programs and regulates alloimmunity [RNAseq 2]

Project description:Stemness programs sustain the alloreactive CD8+ T cells pool in epithelial tissues to mediate graft-versus-host disease (GVHD). Despite suppressing T cell activation, pan Ca2+ signaling inhibition treatment retains stemness programs, and cannot prevent GVHD development in the chronic stage while enhances risks for tumor relapse and infection. Whether specific Ca2+ channels dictate T cell alloreactivity remains to be uncovered. Here we show the mitochondrial calcium uniporter (MCU) regulates stemness programs in alloreactive CD8+ T cells. Genetic ablation of Mcu impaired the transcription of stemness genes and promoted alloreactive CD8+ T cell exhaustion development. Mechanistically, Mcu deficiency increased NF-κB activity during TCR stimulation, enhanced CD25 level hence the sensitivity to IL2. After activation, Mcu expression was intrinsically tuned back to baseline level. Ectopic expression of Mcu decreased the expression of pro-survival stemness genes and enhanced restimulation-induced cell death (RICD), abrogating alloreactive CD8+ T cell GVHD-inducing capacity. Pharmacological enhancement of MCU function with the FDA approved anti-malaria drug artesunate reduced GVHD but spared anti-leukemia potency. These findings unravel MCU controls stemness programs in alloreactive CD8+ T cells, highlighting the translational potential of MCU-targeting genetic or pharmacological approaches in the modulation of T cell alloimmunity.

2026-08-31 | GSE306363 | GEO

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Ezh2 and intracellular Ca2+ signals interdependently coordinate GVHD and CAR T cell responses [RNA-seq_1]

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Mitochondrial Calcium Uniporter modulates CD8+ T cell stemness programs and regulates alloimmunity [RNAseq 1]

Project description:Mitochondrial Calcium Uniporter modulates CD8+ T cell stemness programs and regulates alloimmunity [RNAseq 1]

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Mitochondrial Calcium Uniporter modulates CD8+ T cell stemness programs and regulates alloimmunity [RNAseq 2]

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