Nucleobase Adducts Bind MR1 and Stimulate MR1-Restricted T Cells

Medical Laboratory Science Rheumatology and Immunology Gastroenterology Medicine Cell Biology Oncology Life Sciences Immunology
nucleobase adducts mr1 t cells tumor cells carbonyl stress metabolic changes antigens

Nucleotide Base Adducts Bind MR1 and Stimulate MR1-Restricted T Cells

Abstract

This article provides an overview of the latest research by Vacchini et al. on MR1-restricted T cells (MR1T cells), which discovered the presence of nucleotide base adducts as MR1T cell antigens and unveiled their metabolic pathways and physiological functions in tumor cells. The research is significant for understanding the role of MR1T cells under physiological and pathological conditions and their therapeutic potential.

Research Background

MR1T cells are a newly discovered subset of T cells that can recognize self-antigens presented by MR1 molecules without relying on microbial infection. Currently, the nature of MR1T cell self-antigens remains unclear, impeding our understanding of their physiological functions and therapeutic potential. This study combines genetic, pharmacological, and biochemical methods to reveal how MR1T cells monitor metabolic changes in target cells, providing important insights for functional studies of MR1T cells.

Paper Information

This study was published in the journal Science Immunology on May 10, 2024, titled “Nucleotide Base Adducts Bind MR1 and Stimulate MR1-Restricted T Cells.” The main authors include Alessandro Vacchini, Andrew Chancellor, Qinmei Yang, among others. The research institutions involved include the University Hospital Basel and the University of Basel, ETH Zurich, and others.

Research Process

Gene Screening and Functional Validation

  1. Genome-wide CRISPR-Cas9 Screening: The research team used CRISPR-Cas9 technology to conduct genome-wide gene knockout screening, identifying genes playing crucial roles in tumor cell susceptibility. By sequencing single-guide RNAs in surviving cells, 243 enriched guide RNAs were selected, which might help target cells evade immune destruction.

  2. Gene Verification and Metabolic Pathway Analysis: Verification of the screened genes revealed that nucleotide base metabolic pathways and oxidative phosphorylation play key roles in MR1T cell recognition.

  3. Single-Gene Knockout and Metabolic Response Prediction: Using the Recon3D genome-scale model to predict metabolic network responses, multiple gene knockouts were found to lead to similar metabolic responses, further supporting the metabolic mechanism of MR1T cell recognition.

Recognition of Nucleotide Bases and Nucleoside Antigens

  1. Target Cell Treatment: Different nucleosides, nucleotides, and nucleotide base compounds were co-cultured with cells, and MR1T cell clones showed responses to specific compounds.

  2. Pharmacological Synergy Testing: The use of drugs to inhibit key metabolic enzymes showed that the MR1T cell-stimulating capacity of drug-treated cells significantly increased, confirming the importance of these metabolic pathways in MR1T cell activation.

Major Findings

Metabolic Stress and MR1T Cell Activation

  1. Glycolysis and Methylglyoxal Metabolism: Knockout of glycolytic enzymes or methylglyoxal-degrading enzymes resulted in the accumulation of methylglyoxal in cells and increased MR1T cell stimulating capacity.

  2. Oxidative Stress-Related Carbon Metabolites: Drug-induced accumulation of reactive oxygen species (ROS) in cells promoted MR1T cell activation. Further experiments indicated that carbon adducts generated by ROS-induced lipid peroxidation bind to MR1, serving as MR1T cell antigens.

  3. Binding of Nucleotide Base Adducts to MR1: High-performance liquid chromatography and high-resolution mass spectrometry analysis showed that several nucleotide base adducts, including ethyl adenosine and single guanosine, bound to MR1 and significantly increased under metabolic stress.

Stimulatory Effects of Nucleotide Base Adducts on MR1T Cells

  1. Synthetic Analog Testing: Synthesized the detected nucleotide base adducts and demonstrated in experiments that these synthesized compounds could upregulate MR1 surface expression and stimulate specific MR1T cell clones.

  2. MR1 Tetramers for Cell Recognition: Prepared MR1 tetramers loaded with different antigens to detect MR1T cells in peripheral blood and tumor-infiltrating lymphocytes. Results showed that specific MR1T cells could recognize these adducts.

Conclusion and Significance

This study reveals for the first time the self-antigen properties of MR1T cells in humans, indicating that these antigens are primarily nucleotide base adducts formed by carbon metabolism. This discovery expands our understanding of T cell antigen recognition and reveals the physiological and pathological mechanisms through which MR1T cells monitor the metabolic integrity of target cells. Especially in tumor cells, due to significant changes in their metabolic pathways, MR1T cell antigens are more easily generated, offering new perspectives on the potential application of MR1T cells in tumor immunotherapy.

Research Highlights

  1. Discovery of MR1T Cell Antigens: Through genomic screening and metabolic pathway analysis, identified nucleotide base adducts as MR1T cell antigens.
  2. Key Role of Metabolic Stress: Revealed the synergistic roles of glycolysis, oxidative stress, and nucleotide base metabolism in MR1T cell activation.
  3. Novel Tetramer Tools: Developed MR1 tetramers with nucleotide base adducts for detecting and studying MR1T cells.

Future Prospects

Further elucidate the specific roles of MR1T cells under physiological and pathological conditions and explore their potential applications in tumor immunotherapy. This will provide a theoretical basis and technical support for developing new immunotherapies based on MR1T cells.