Deficient leptin receptor signaling in T cells of human SLE

Ting Liu; Ming Zheng; Li Jia; Mingyuan Wang; Longhai Tang; Zhenke Wen; Miaojia Zhang; Fenghong Yuan

doi:10.3389/fimmu.2023.1157731

Deficient leptin receptor signaling in T cells of human SLE

Front Immunol. 2023 Mar 17:14:1157731. doi: 10.3389/fimmu.2023.1157731. eCollection 2023.

Authors

Ting Liu^{1

2}, Ming Zheng³, Li Jia³, Mingyuan Wang⁴, Longhai Tang⁴, Zhenke Wen³, Miaojia Zhang², Fenghong Yuan¹

Affiliations

¹ Department of Rheumatology, the Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
² Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
³ Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
⁴ Department of Research Center, Suzhou Blood Center, Suzhou, China.

Abstract

Background: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease mainly mediated by IgG autoantibody. While follicular helper T (Tfh) cells are crucial for supporting IgG autoantibody generation in human SLE, underlying mechanisms for Tfh cell mal-differentiation remain unclear.

Methods: In total, 129 SLE patients and 37 healthy donors were recruited for this study. Circulating leptin was determined by ELISA from patients with SLE and healthy individuals. CD4 T cells isolated from SLE patients and healthy donors were activated with anti-CD3/CD28 beads under cytokine-unbiased conditions in the presence or absence of recombinant leptin protein, followed by detection for Tfh cell differentiation by quantifying intracellular transcription factor Bcl-6 and cytokine IL-21. AMPK activation was assessed by analyzing phosphor-AMPK using phosflow cytometry and immunoblots. Leptin receptor expression was determined using flow cytometry and its overexpression was achieved by transfection with an expression vector. Humanized SLE chimeras were induced by injecting patients' immune cells into immune-deficient NSG mice and used for translational studies.

Results: Circulating leptin was elevated in patients with SLE, inversely associated with disease activity. In healthy individuals, leptin efficiently inhibited Tfh cell differentiation through inducing AMPK activation. Meanwhile, leptin receptor deficiency was a feature of CD4 T cells in SLE patients, impairing the inhibitory effect of leptin on the differentiation of Tfh cells. As a result, we observed the coexistence of high circulating leptin and increased Tfh cell frequencies in SLE patients. Accordingly, overexpression of leptin receptor in SLE CD4 T cells abrogated Tfh cell mal-differentiation and IgG anti-dsDNA generation in humanized lupus chimeras.

Conclusion: Leptin receptor deficiency blocks the inhibitory effect of leptin on SLE Tfh cell differentiation, serving as a promising therapeutic target for lupus management.

Keywords: AMPK; SLE; T cell; leptin; leptin receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Autoantibodies
Humans
Immunoglobulin G / metabolism
Leptin / metabolism
Lupus Erythematosus, Systemic*
Mice
Receptors, Leptin / genetics
Receptors, Leptin / metabolism
T-Lymphocytes, Helper-Inducer*

Substances

Receptors, Leptin
Leptin
AMP-Activated Protein Kinases
Autoantibodies
Immunoglobulin G

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (82071826, 82271841), Natural Science Foundation of Jiangsu Province (BK20211542, BK20201407), Jiangsu Specially-Appointed Professor Program, Suzhou Municipal Science and Technology Bureau (ZXL2022460), Major Project of Natural Science Research in Jiangsu Higher Education Institutions (22KJA310005), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Suzhou Municipal Health Commission (SZXK202118, GWZX202004).