Human γδ T Cells in Diverse Tissues Exhibit Site-Specific Maturation Dynamics Across the Life Span

Research Background

γδ T cells play an important role in the immune system, particularly in protective immunity, homeostasis, and tissue repair. Unlike conventional αβ T cells, which are restricted by major histocompatibility complex (MHC), γδ T cells directly seed peripheral tissues and respond to various microbial stimuli without relying on MHC-peptide recognition. In mouse models, the development of γδ T cells occurs in “waves” that localize to barrier sites at critical developmental time points. These studies provide clues to the pivotal role of γδ T cells during early development. However, the role of human γδ T cells in peripheral tissues remains unclear, as most studies focus primarily on blood and the thymus. Given their roles in tumor and certain pathogen immune responses, understanding their functional and distribution dynamics across different age stages and tissues is necessary.

Source of the Paper

This research paper titled “Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the lifespan” is co-authored by researchers from Columbia University, University of Cambridge, University of California, Berkeley, and University of Florida. The paper was published in the journal Science Immunology under article number eadn3954 on June 7, 2024.

Research Process

To deeply study the function and distribution of human γδ T cells in different tissues, we conducted the following research processes and experiments:

  1. Sample Collection and Processing:

    • We collaborated with multiple organ procurement organizations (OPOs) in the USA to obtain blood, spleen, lung, jejunum, related lymph nodes from 124 organ donors (including 70 children and 54 adults), and an additional 52 blood samples.
    • The samples were analyzed using high-dimensional methods such as flow cytometry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing after mechanical and enzymatic processing.
  2. Experimental Methods and Analysis:

    • Flow Cytometry: Used to analyze the proportion and functional markers of γδ T cells in different organs.
    • Single-cell RNA Sequencing: Identified γδ T cell subpopulations at different developmental stages and compared their gene expression profiles.
    • TCR Sequencing: Analyzed TCR gene usage patterns and clonal expansion of γδ T cells, measuring the clonal overlap of γδ T cells across different tissues and age-related changes.
  3. Data Processing:

    • Data processing employed efficient computational biology methods, utilizing Python and R programming for data cleaning, dimensionality reduction, and differential expression analysis. γδ T cell subtype identification and functional classification were performed using a multi-modal classifier (MMOCHI).

Main Results

  1. Differences in the Proportion and Function of γδ T Cells in Children’s and Adults’ Tissues:

    • The proportion of γδ T cells in the blood, spleen, and lung of children is significantly higher than that in adults.
    • Children’s γδ T cells exhibit pronounced tissue repair functions, while adult γδ T cells predominantly show cytotoxic characteristics.
  2. Tissue-specific Distribution of γδ T Cell Subpopulations:

    • In children, Vδ1 cells are primarily distributed in the spleen, jejunum, and lymph nodes, while in adults, Vδ1 cells dominate in all tissues, and Vδ2 cells are mainly present in the blood.
    • During the antigen exposure-driven maturation process, γδ T cells exhibit different functional states.
  3. Clonal Expansion and Distribution Patterns:

    • TCR sequencing shows significant differences in clonal diversity and expansion of γδ T cells across different tissues and age groups.
    • γδ T cells in children have more diverse clones, while in adults, γδ T cells show greater clonal expansion and higher overlap across multiple tissues.

Conclusion and Significance

This study reveals the functional and distribution characteristics of human γδ T cells in different tissues throughout life, highlighting significant changes from childhood to adulthood. In the pediatric stage, γδ T cells in tissues are in an immature state important for tissue repair and immune protection. Conversely, in adulthood, γδ T cells exhibit highly differentiated and cytotoxic characteristics, more suitable for immune surveillance.

This transformation not only uncovers potential biological mechanisms during the developmental process of γδ T cells but also provides important theoretical basis for developing immunotherapy strategies tailored to different age groups and disease contexts.

Research Highlights

  1. Lifecycle Coverage of γδ T Cell Dynamics: Integrated analysis of organ donors and blood samples from different age stages reveals the dynamic changes of γδ T cells throughout the lifecycle.
  2. High-dimensional Data Integration Analysis: Combining flow cytometry, single-cell RNA sequencing, and TCR sequencing systematically demonstrates the functional heterogeneity and clonal distribution of γδ T cells.
  3. Antigen-driven Clonal Expansion: Clonal analysis shows the characteristics of antigen-driven expansion of γδ T cells across different ages and tissues.

Future Research Directions

  • Further analysis of the functional changes of γδ T cells under different disease states and environments.
  • Study of key transcription mechanisms during γδ T cell development to identify potential immunotherapy targets.

This research not only deepens our understanding of the dynamic distribution and function of human γδ T cells throughout life but also provides valuable foundational data and research directions for developing more effective immunotherapies in the future.