Gfi1b Specifies Developmental Potential of Innate Lymphoid Cell Progenitors in the Lungs

Rheumatology and Immunology Microbiology Respiratory System Life Sciences Immunology Medicine Cell Biology
Gfi1b lungs innate lymphoid cells developmental potential progenitor cells immunity

Background Introduction

In respiratory diseases, the lung is a sensitive organ exposed to the external environment, making it susceptible to pathogens, allergens, and toxic particles. Due to the high morbidity and mortality associated with respiratory diseases (such as asthma), it is crucial to study the mechanisms protecting the cells on the surface of the lung mucosa. Innate Lymphoid Cells (ILCs) play a significant role in this defense, especially type 2 ILCs (ILC2s), which are key players in defending against pulmonary pathogens. They drive pathological responses to inhaled allergens such as house dust mites and regulate immune responses in asthma.

Research Motivation

However, the factors regulating the development of pulmonary ILC2s remain unclear. The fate mapping analysis of the transcription factors Gfi1 and Gfi1b suggests that Gfi1 maintains constant expression during the development of ILC2s, while Gfi1b expression is confined to specific types of bone marrow precursor cells and pulmonary ILC progenitors. Therefore, the authors aim to explore the role of Gfi1b in the multipotency and development of tissue-specific ILC2s.

Research Source

This paper was completed by researchers from multiple institutions and was published in the Science Immunology journal on May 31, 2024. The main authors include Qiutong Huang, Wang H. J. Cao, and Sophie Curio, from the Frazer Institute at the University of Queensland, the Walter and Eliza Hall Institute of Medical Research, and the University of Melbourne.

Research Methods

Experimental Procedures

  1. Establishment of Experimental Models:

    Utilized dual-reporter mice (Gfi1b-GFP and Gfi1-tdTomato) for expression mapping of ILC2 progenitor cells in the bone marrow. In these mice, Gfi1b-GFP and Gfi1-tdTomato mark the expression of Gfi1b and Gfi1, respectively.

  2. Cell Sorting and Transfer Experiments:

    Isolated Gfi1b-GFP+ and Gfi1-tdTomato+ cells from the bone marrow of these dual-reporter mice and subsequently transferred them into sub-lethally irradiated Rag2-/- Il2rg-/- mice. Six weeks later, the tissues of the recipient mice were analyzed to determine the lineage trajectory of these cells.

  3. Single-Cell RNA Sequencing:

    Conducted single-cell RNA sequencing (10x single-cell RNA-seq) on various types of IL-18R+ cells and classical lung ILC2s, comparing the transcriptomes of Gfi1b-GFP+ and Gfi1b-GFP- cells.

  4. Functional Identification:

    Verified the protective role of Gfi1b+ lung progenitor cells in inducing inflammatory responses and tumor invasion. Experiments included acute inflammation induction (e.g., intranasal administration of papain) and pulmonary metastasis models of melanoma cells B16F10.

Data Analysis and Algorithm

In the data analysis, various bioinformatics analysis methods were applied, including gene expression ranking, GO enrichment analysis, and cell cycle analysis, to comprehensively understand the regulation of Gfi1b on the development of local pulmonary ILCs.

Main Research Results

  1. Differential Expression of Gfi1 and Gfi1b:

    The experimental results showed that Gfi1 is expressed to varying degrees in all types of ILCs, whereas Gfi1b expression is limited to specific bone marrow precursor cells and ILCs in specific tissues such as the lung and liver.

  2. Multipotency of Gfi1b+ Cells:

    Gfi1b+ lung ILC progenitor cells demonstrated significant multipotency, capable of differentiating into various ILC types, including effector ILC2s in the lungs and ILC1s in liver tissue.

  3. Gene Expression Characteristics:

    Gfi1b+ IL-18R+ lung ILC2s showed significantly different gene expression profiles compared to other ILC groups, exhibiting rich regulatory genes, including key genes that regulate stem cell-like characteristics and ILC development.

  4. Role of Gfi1b in Maintaining Bone Marrow ILC Progenitor Cells:

    The absence of Gfi1b in the bone marrow led to selective loss of ILC progenitor cells and a significant reduction of local lung ILC2s, while ILC2s in other peripheral tissues were not significantly affected.

  5. Functional Verification:

    Gfi1b-deficient mice were significantly weaker in responding to acute inflammation and lung tumor invasion compared to normal wild-type mice, indicating that Gfi1b plays an important role in maintaining local pulmonary immune stability.

Conclusions and Significance

This study comprehensively validated the specific expression and multipotency of Gfi1b in local lung ILC progenitor cells, revealing the critical regulatory role of Gfi1b in the development and maintenance of lung ILCs. These findings not only deepen our understanding of ILC development mechanisms but also provide important references for treating pulmonary immune diseases.

Research Highlights

  • Innovation:

    This study is the first to elucidate the specific expression and function of Gfi1b in lung ILC2 progenitor cells, providing new insights into the development of tissue-specific ILCs.

  • Applied Value:

    The findings could provide potential new targets and new immunotherapeutic approaches for treating respiratory diseases such as asthma and lung cancer.

  • Scientific Significance:

    This research not only reveals the unique gene expression and developmental regulatory mechanisms of tissue-restricted lung ILC2s but also provides important references for further exploration of the developmental regulation of other tissue-specific immune cells.

This study is of significant importance to basic immunology research and may also have profound implications for diagnosing and treating clinical diseases.