Scientists at the La Jolla Institute for Immunology (LJI) have produced one of the most detailed maps yet of immune cells living inside human lungs, revealing how local immune activity may connect inherited genetic risk to autoimmune and lung disease. In a study published in Nature Immunology, the researchers analyzed more than 1.1 million immune cells collected from lung tissue donated by 128 people. Their findings suggest that tissue-resident immune cells—long-lived cells that remain embedded in organs rather than circulating through the bloodstream—may not simply respond to disease. In some individuals, they may help initiate or sustain the inflammation that drives it.
The study focused on healthy-appearing lung tissue removed during surgery from patients newly diagnosed with lung cancer. The samples were collected through the Target Lung study, led by researchers at the University of Liverpool, and were accompanied by extensive clinical information. Although the volunteers had lung cancer, the tissue analyzed was not necessarily cancerous, allowing the investigators to examine immune cells in their local tissue environment. This distinction was important because immune cells can behave very differently inside organs than they do in blood samples routinely used for immunological research.
Tissue-resident immune cells form a specialized defense network throughout the lungs. They include multiple types of T cells, macrophages, natural killer cells, and other leukocytes that monitor the airways and lung tissue for infectious organisms, damaged cells, and abnormal growth. Their permanent residence allows them to respond rapidly to respiratory threats, but it also exposes them to the possibility of becoming chronically activated. When immune regulation fails, these cells can release inflammatory signals, damage healthy tissue, or recruit additional immune cells, potentially contributing to conditions such as rheumatoid arthritis, lupus, and scleroderma, all of which can involve persistent lung inflammation.
To determine how these cells function, the LJI team used single-cell RNA sequencing, or single-cell RNA-seq. The technique measures the messenger RNA molecules inside individual cells, providing a snapshot of which genes are active at a particular moment. Rather than averaging gene activity across millions of cells, as conventional bulk RNA sequencing does, single-cell analysis can distinguish closely related immune-cell populations and identify rare cellular states. The researchers combined these expression profiles with genetic information to investigate whether inherited DNA variants influenced immune-cell behavior specifically within lung tissue.
The analysis identified approximately 1,000 genes whose activity in lung-resident immune cells was shaped by genetic variation. These gene-regulatory effects were not detected in the same way in immune cells examined from blood. The result indicates that a disease-associated genetic variant may have consequences only in the right cellular and tissue context. A variant that appears relatively silent in circulating cells could alter gene expression in a lung-resident macrophage or T cell, for example, changing how that cell responds to infection, tissue damage, or inflammatory signals. This tissue-specific genetic regulation may help explain why the biological effects of disease-risk variants can be difficult to detect in standard blood-based studies.
The researchers describe these findings as evidence that tissue-resident immune cells can act as intermediaries between genetic susceptibility and disease. Genes linked to autoimmune risk may influence the threshold at which an immune cell becomes activated, the intensity of its inflammatory response, or its ability to return to a resting state after a threat has passed. Over time, such changes could produce an environment in which inflammation persists even without an ongoing infection. The study does not establish that the identified cells directly cause autoimmune disease, but it provides a large-scale molecular framework for testing that possibility in future experiments and patient studies.
The dataset also exposed pronounced biological differences between female and male volunteers. Around 1,700 genes showed sex-associated differences in expression within lung tissue-resident immune cells. Several of these genes were connected to cellular pathways involved in inflammation and immune activation. The observation may be relevant to the longstanding epidemiological pattern in which many autoimmune diseases are more common in women. Sex-biased gene activity could affect how immune cells recognize danger, communicate with neighboring cells, or control inflammatory reactions. However, the researchers emphasize that these patterns represent potential mechanisms rather than a complete explanation for sex differences in autoimmune disease.
The scale of the investigation was made possible through the Database of Immune Cell Epigenomics, known as DICE, a resource designed to connect human genetic variation with immune-cell function. By incorporating participants with different ages, sexes, and genetic backgrounds, DICE allows researchers to compare how the same immune-cell type behaves across individuals. The lung study expands that resource beyond the circulating immune cells most commonly analyzed in clinical research. It also demonstrates why sampling the tissue where disease begins may be essential for understanding complex disorders whose genetic signals are distributed across many genes and cell types.
Further work will be needed to determine whether the gene-expression patterns observed in these lung samples predict future disease, reflect early effects of cancer or surgery, or directly drive autoimmune inflammation. Researchers will need to validate the findings in people with established rheumatoid arthritis, lupus, and other lung-associated autoimmune conditions, as well as in longitudinal studies that track immune-cell behavior over time. Even with these limitations, the study offers a detailed view of how local immune ecosystems may translate inherited risk into organ-specific disease. It suggests that the next generation of autoimmune research may depend not only on identifying risky genes, but also on discovering where, when, and in which cells those genes become active.
Subject of Research: Cells
Article Title: Tissue-resident immune cells drive genetic risk in autoimmune and lung diseases
News Publication Date: 3-Aug-2026
Web References: https://www.nature.com/articles/s41590-026-02596-2; https://doi.org/10.1038/s41590-026-02596-2
References: Nature Immunology; Gonzalez-Colin et al., “Tissue-resident immune cells drive genetic risk in autoimmune and lung diseases”
Keywords: tissue-resident immune cells, lung immunity, autoimmune disease, rheumatoid arthritis, lupus, scleroderma, inflammation, single-cell RNA sequencing, genetic risk, immunogenetics, sex differences, lung disease
