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Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
Long-term glucocorticoid exposure persistently impairs CD4+ T cell biology by epigenetically modulating the mTORC1
Huihui Chen1, Chongqing Tan2, Zhiruo Wang3
1Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Clinical Immunology Research Center of Central South University, Changsha, China.
Abstract:
Conventional glucocorticoid (GC) treatment has a long-term influence on T-cell immunity, resulting in an increased risk of opportunistic infection after drug withdrawal. The underlying mechanisms remain ambiguous. This study demonstrated that long-term GC treatment induced persistent lymphopenia in patients with primary glomerular disease. GCs continuously suppressed the proportion of CD4+ T cells even after the daily dose was tapered down to the physiologic equivalences, leading to a significant decline of the CD4/CD8 ratio. Meanwhile, GCs impaired CD4+ T cell biology, leading to enhanced apoptotic cell death, reduced proliferative capacity, downregulated pro-inflammatory genes, and upregulated immunoregulatory genes. Specifically, GCs altered FOXP3 expression pattern in CD4+ T cells and favored their acquisition of an active T regulatory (Treg) cell phenotype with enhanced IL-10 production upon stimulation. Mechanistically, GCs tampered with the transcriptional regulation of mechanistic target of rapamycin complex 1 (mTORC1) pathway, resulting in an inhibitory impact on the signaling activity. Targeting mTORC1 signaling by siRNAs could sufficiently modify the viability of GC-exposed CD4+ T cells. By high-throughput sequencing of genome-wide DNA methylation and mRNA, we further uncovered a causal relationship between the altered DNA methylation level and transcription activity in a subset of mTORC1 pathway genes in long-term GC exposure. Taken together, this study reveals a novel regulation of mTORC1 signaling, which might dominate the long-term influence of GC on CD4+ T cell biology in a dose-independent manner.
Insights
Long-term glucocorticoid (GC) treatment persistently impairs T-cell immunity by suppressing CD4+ T cells and altering their function. This immune suppression, linked to the mTORC1 pathway, occurs even at low doses, increasing infection risk.
Area of Science:
- Immunology
- Pharmacology
- Molecular Biology
Background:
- Conventional glucocorticoid (GC) therapy can lead to long-term T-cell immune dysfunction and increased opportunistic infection risk post-treatment.
- The precise mechanisms behind this persistent immune suppression remain incompletely understood.
Purpose of the Study:
- To investigate the long-term effects of glucocorticoid treatment on T-cell immunity in patients with primary glomerular disease.
- To elucidate the molecular mechanisms underlying glucocorticoid-induced T-cell alterations, focusing on CD4+ T cells and the mTORC1 pathway.
Main Methods:
- Analysis of T-cell populations (CD4+, CD8+) and CD4/CD8 ratio in patients undergoing long-term GC treatment.
- Assessment of CD4+ T-cell function, including apoptosis, proliferation, gene expression (pro-inflammatory and immunoregulatory), and FOXP3/Treg cell phenotype.
- Mechanistic studies involving the mechanistic target of rapamycin complex 1 (mTORC1) pathway, siRNA targeting, and high-throughput sequencing (DNA methylation, mRNA).
Main Results:
- Long-term GC treatment induced persistent lymphopenia and suppressed CD4+ T-cell proportion, significantly reducing the CD4/CD8 ratio, even at low doses.
- GCs impaired CD4+ T-cell biology, increasing apoptosis, reducing proliferation, downregulating pro-inflammatory genes, and upregulating immunoregulatory genes, promoting an active T regulatory (Treg) phenotype with enhanced IL-10 production.
- GCs inhibited mTORC1 signaling activity, and targeting mTORC1 could restore viability of GC-exposed CD4+ T cells. Genome-wide methylation and mRNA sequencing revealed a causal link between altered DNA methylation and transcription of mTORC1 pathway genes.
Conclusions:
- Long-term glucocorticoid exposure causes persistent CD4+ T-cell lymphopenia and functional impairment, mediated by mTORC1 pathway dysregulation.
- The study reveals a novel, dose-independent regulation of mTORC1 signaling by GCs, which significantly impacts CD4+ T-cell biology and may explain long-term immune suppression and infection risk.
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