Spatial analyses: Focusing on immune-stromal interactions to understand immunity in the tissue context

Immune cells perform their tasks in tissues, thus, they are highly dependent on their microenvironment. This means that the tissue context should be considered to fully understand their function. For a long time, it has been difficult to quantify these complex interrelationships in tissues and to spatially map the diversity of cell types involved. In recent years, several methods have become available that allow comprehensive profiling of immune cells and their microenvironment, at both the protein and transcriptional levels. We have used multiplex immunofluorescence histology in combination with machine-learning based cell segmentation and annotation to identify even rare immune cell populations, namely innate lymphoid cells, in various human tissues and found that they preferentially localize in fibrovascular niches. Those niches are located around blood vessels, enriched in stromal cells and extracellular matrix, and represent a location for innate lymphoid cells across various organs. By combining multiplexed histology and spatial transcriptomics on serial sections, we further identified those tissue areas as seed points for COVID-19 induced lung fibrosis and pin-pointed a pro-fibrotic macrophage population as driver of this process, leading to an expansion of the niches. At later disease stages, these areas were populated by lymphocytes, promoting the formation of tertiary lymphoid structures. Whether similar mechanisms apply to other diseases associated with fibrosis, such as autoimmune conditions, awaits further investigation.