The kinetics of mTORC1 activation associates with FOXP3 expression pattern of CD4+ T cells and outcome of steroid-sensitive minimal change disease

Guochun Chen; Mengru Zeng; Zhiwen Liu; Mi Zhou; Jie Zha; Lei Zhang; Huihui Chen; Hong Liu

doi:10.1016/j.intimp.2023.110589

The kinetics of mTORC1 activation associates with FOXP3 expression pattern of CD4+ T cells and outcome of steroid-sensitive minimal change disease

Int Immunopharmacol. 2023 Sep:122:110589. doi: 10.1016/j.intimp.2023.110589. Epub 2023 Jul 5.

Authors

Guochun Chen¹, Mengru Zeng², Zhiwen Liu², Mi Zhou², Jie Zha², Lei Zhang², Huihui Chen³, Hong Liu⁴

Affiliations

¹ Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, China; Clinical Immunology Research Center of Central South University, Changsha, China. Electronic address: guochunchen@csu.edu.cn.
² Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, China.
³ Clinical Immunology Research Center of Central South University, Changsha, China; Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, China. Electronic address: chenhuihuiliko@gmail.com.
⁴ Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, China. Electronic address: liuhong618@csu.edu.cn.

PMID: 37418986
DOI: 10.1016/j.intimp.2023.110589

Abstract

Minimal change disease (MCD) usually responds to glucocorticoids (GCs) but relapses in most cases. Relapse pathogenesis after complete remission (CR) remains unclear. We hypothesized that FOXP3⁺ T regulatory cell (Treg) dysregulation may drive early relapses (ER). In this study, a cohort of 23 MCD patients were treated with a conventional GC regimen for the initial onset of nephrotic syndrome. Upon GC withdrawal, seven patients suffered from ER, while 16 patients sustained remission (SR) during the 12-month follow-up. Patients with ER had reduced FOXP3⁺ Treg proportions compared with healthy controls. Treg reduction, accompanied by IL-10 impairment, was ascribed to a proportional decline of FOXP3^medium rather than FOXP3^high cells. GC-induced CR was marked by a rise in the proportions of FOXP3⁺ and FOXP3^medium cells compared to baseline levels. These increases declined in patients with ER. The expression level of phosphorylated ribosomal protein S6 was used to track the dynamic shifts in mTORC1 activity within CD4+ T cells of MCD patients at various stages of treatment. Baseline mTORC1 activity was inversely correlated with FOXP3⁺ and FOXP3^medium Treg proportion. The mTORC1 activity in CD4+ T cells served as a reliable indicator for ER and demonstrated improved performance when paired with FOXP3 expression. Mechanically, targeting mTORC1 intervention by siRNAs sufficiently altered the conversion pattern of CD4⁺ T cell to FOXP3⁺ Treg. Taken together, the activity of mTORC1 in CD4+ T cells can act as a credible predictor for ER in MCD, especially when combined with FOXP3 expression, and may offer a potential therapeutic avenue for the treatment of podocytopathies.

Keywords: FOXP3; Glucocorticoid; Minimal change disease; Nephrotic syndrome; Podocytopathy; mTOR complex 1; regulatory T cell.

MeSH terms

CD4-Positive T-Lymphocytes* / metabolism
Forkhead Transcription Factors / metabolism
Humans
Kinetics
Mechanistic Target of Rapamycin Complex 1 / metabolism
Nephrosis, Lipoid* / drug therapy
Nephrosis, Lipoid* / metabolism
Recurrence
Steroids
T-Lymphocytes, Regulatory / metabolism

Substances

Mechanistic Target of Rapamycin Complex 1
Steroids
Forkhead Transcription Factors
FOXP3 protein, human