Department of Ophthalmology, the Second Xiangya Hospital of Central South University, Changsha, China; Clinical Immunology Research Center of Central South University, Changsha, China.
Department of Pharmacy, the Second Xiangya Hospital of Central South University, Changsha, China.
Biochem Pharmacol. 2023 May;211:115503. doi: 10.1016/j.bcp.2023.115503. Epub 2023 Mar 15.
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.
传统糖皮质激素（GC）治疗对 T 细胞免疫有长期影响，导致停药后机会性感染的风险增加。其潜在机制仍不清楚。本研究表明，长期 GC 治疗可诱导原发性肾小球疾病患者持续淋巴细胞减少。即使将每日剂量减少至生理等效剂量，GC 仍持续抑制 CD4+T 细胞的比例，导致 CD4/CD8 比值显著下降。同时，GC 损害 CD4+T 细胞生物学功能，导致凋亡细胞死亡增加、增殖能力降低、促炎基因下调和免疫调节基因上调。具体而言，GC 改变了 CD4+T 细胞中 FOXP3 的表达模式，并有利于其获得活跃的 T 调节（Treg）细胞表型，刺激后 IL-10 产生增加。在机制上，GC 干扰了雷帕霉素复合物 1（mTORC1）通路的转录调控，从而对信号活性产生抑制作用。通过 siRNA 靶向 mTORC1 信号通路可以充分改变 GC 暴露的 CD4+T 细胞的活力。通过全基因组 DNA 甲基化和 mRNA 的高通量测序，我们进一步发现了在长期 GC 暴露中，mTORC1 通路基因的一部分改变的 DNA 甲基化水平与转录活性之间存在因果关系。综上所述，该研究揭示了 mTORC1 信号的一种新调控机制，可能以非剂量依赖的方式主导 GC 对 CD4+T 细胞生物学的长期影响。
