Elucidating T cell dynamics and molecular mechanisms in syngeneic and allogeneic islet transplantation through single-cell RNA sequencing

Front Immunol. 2024 Jul 19:15:1429205. doi: 10.3389/fimmu.2024.1429205. eCollection 2024.

Abstract

Islet transplantation is a promising therapy for diabetes treatment. However, the molecular underpinnings governing the immune response, particularly T-cell dynamics in syngeneic and allogeneic transplant settings, remain poorly understood. Understanding these T cell dynamics is crucial for enhancing graft acceptance and managing diabetes treatment more effectively. This study aimed to elucidate the molecular mechanisms, gene expression differences, biological pathway alterations, and intercellular communication patterns among T-cell subpopulations after syngeneic and allogeneic islet transplantation. Using single-cell RNA sequencing, we analyzed cellular heterogeneity and gene expression profiles using the Seurat package for quality control and dimensionality reduction through t-SNE. Differentially expressed genes (DEGs) were analyzed among different T cell subtypes. GSEA was conducted utilizing the HALLMARK gene sets from MSigDB, while CellChat was used to infer and visualize cell-cell communication networks. Our findings revealed genetic variations within T-cell subpopulations between syngeneic and allogeneic islet transplants. We identified significant DEGs across these conditions, highlighting molecular discrepancies that may underpin rejection or other immune responses. GSEA indicated activation of the interferon-alpha response in memory T cells and suppression in CD4+ helper and γδ T cells, whereas TNFα signaling via NFκB was particularly active in regulatory T cells, γδ T cells, proliferating T cells, and activated CD8+ T cells. CellChat analysis revealed complex communication patterns within T-cell subsets, notably between proliferating T cells and activated CD8+ T cells. In conclusion, our study provides a comprehensive molecular landscape of T-cell diversity in islet transplantation. The insights into specific gene upregulation in xenotransplants suggest potential targets for improving graft tolerance. The differential pathway activation across T-cell subsets underscores their distinct roles in immune responses posttransplantation.

Keywords: T-cell; allotransplantation; diabetes; immune tolerance; immunomodulation; islet transplantation; single-cell RNA sequencing; transplant rejection.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology
  • Gene Expression Profiling
  • Graft Rejection / genetics
  • Graft Rejection / immunology
  • Graft Survival / genetics
  • Graft Survival / immunology
  • Islets of Langerhans Transplantation*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Sequence Analysis, RNA
  • Single-Cell Analysis* / methods
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Transcriptome
  • Transplantation, Homologous*
  • Transplantation, Isogeneic

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by the Shenzhen Science and Technology Program (JCYJ20230807115107015, GCZX2015043017281705), Team-based Medical Science Research Program (2024YZZ04), the Natural Science Foundation of China (82170794), Innovation and Technology Bureau of Longhua, Shenzhen. Joint Funds for the Innovation of Science and Technolgy, Fujian province (2023Y9281).