Special Report: The Role of Tissue-Resident Memory T Cells in Breaking Self-Antigen Immune Tolerance and Immune-Mediated Nephritis in the Kidney

Introduction

Immune-mediated nephritis is one of the major causes of acute kidney injury and chronic kidney disease. While the role of B cells and antibodies in such diseases has been extensively studied, the emergence of immune checkpoint inhibitors has provided an opportunity to reassess the role of T cells in renal immunology. However, it remains unclear how T cells specific to renal self-antigens are activated and participate in immune-mediated nephritis. This study aims to reveal the fate and function of these T cells, especially the tissue-resident memory T cells (TRM cells) that form and maintain in the kidney.

Research Background

Immune-mediated nephritis is caused by inappropriate immune responses to self-antigens or harmless substances (such as antibiotics), which can lead to kidney function decline and even end-stage renal disease. A large body of existing research has mainly focused on antibody-mediated immune-mediated nephritis, while the role of cellular immunity in immune-mediated kidney disease remains unclear. Cytotoxic CD8+ T lymphocytes (CTLs) are typically present in large numbers in kidney infiltrates and have been shown to play a crucial role in various types of immune-mediated nephritis. These infiltrates are particularly common in forms of interstitial nephritis (such as drug-induced acute interstitial nephritis or immune checkpoint inhibitor-related nephritis). In this context, there is a need for in-depth analysis of cellular immune mechanisms in the kidney.

Research Source

This paper was written by Frederic Arnold and his team from the Department of Medicine IV and Institute of Microbiology and Hygiene, as well as the Institute of Pathology at the University Medical Center Freiburg, Germany, and published in the journal “Cellular & Molecular Immunology” in 2024.

Research Methods and Process

1. Experimental Mouse Model Establishment

   • Animals and Cell Transfer: The study used a new mouse model called NOH (nephrin, ovalbumin, HEL) transgenic mice, which express membrane-bound ovalbumin (OVA) on podocytes. High-affinity OVA-specific T cells (OT-1 cells) were transferred to NOH and wild-type (WT) mice.
   • Immune Activation: After transfer, mice were infected with OVA-Listeria monocytogenes (LM-OVA) within 24 hours to activate OT-1 cells, and received a second vaccination (OVA-Vesicular stomatitis virus, VSV-OVA) on day 21.
   • Monitoring and Analysis: Mice underwent weekly blood and urine analysis, and endpoint analyses were performed at early (day 7) and late (day 35-56) time points, including single-cell transcriptomics, high-dimensional flow cytometry, and multiplex immunofluorescence imaging.

2. Main Research Findings

   • Systemic and Local Immune Response Analysis: After LM-OVA infection and OT-1 cell transplantation, OT-1 cells in NOH mice rapidly decreased after secondary infection but formed persistent local infiltration in the kidney, displaying a mixed phenotype combining features of activation and T cell dysfunction.
   • Persistence of Kidney TRM Cells: TRM cells formed in the kidneys of NOH mice, persisted, and dominated the local immune response. OVA uptake and cross-presentation were detected in renal tubular epithelial cells.
   • Relevance to Human Disease: The research team also found T cells with TRM cell markers in human kidney tissue with interstitial nephritis, supporting the role of these cells in maintaining human renal autoimmunity.

Research Significance and Conclusions

Scientific Value and Application Prospects

This study reveals how tissue-specific immune responses are separated from systemic immune responses and drive compartmentalized immune reactions in mouse and human kidneys. The research suggests that targeting TRM cells may become a new strategy for controlling immune-mediated kidney diseases.

Research Highlights

• Discovery of TRM Cells’ Role in the Kidney: TRM cells can persist locally in the kidney and mediate immune-mediated nephritis, providing new insights into the persistence of autoimmune responses.
• New Experimental Model: A new mouse model was successfully established using OT-1 cells with a mixed phenotype, simulating human immune-mediated kidney disease.
• Strong Translational Potential: The research findings show the potential of targeting TRM cells as an important basis for developing new therapies for immune-mediated kidney diseases.

The study demonstrates that using a strategy of breaking self-antigen immune tolerance with T cells can simulate and explore kidney immune-mediated mechanisms, providing theoretical and practical support for future immunotherapy. This research not only helps the academic community understand the role of TRM cells in autoimmunity but also provides new therapeutic directions for clinical practice.