A new way to read immune cells through their membranes
A new study published in Nature Chemical Biology by researchers from SciLifeLab and Karolinska Institutet (KI) has developed a method for measuring the physical properties of cell membranes in thousands of individual immune cells simultaneously. The study was led by Erdinc Sezgin, SciLifeLab Group Leader and researcher at KI, with Luca Andronico, a KI researcher and member of Sezgin’s research group, as first author.
Every cell is surrounded by a membrane that acts as its protective layer. Traditionally, immune cells are identified by the proteins they carry on their surface, but very little attention has been given to the physical properties of that membrane itself.
In this study, Erdinc Sezgin’s team developed a method that allows them to measure how “fluid” the cell membrane is in thousands of individual immune cells simultaneously. They combine standard flow cytometry, a technology commonly used in hospitals and research laboratories, with a special fluorescent dye that changes its color depending on the physical state of the membrane.
They found that the physical properties of the membrane provide important information about the state and function of immune cells. It can be used to identify immune cell subpopulations with distinct behaviors, including differences in migration and their ability to kill cancer cells.
Looking beyond the cell surface
SciLifeLab was central to the success of this project. The work was highly interdisciplinary and brought together expertise in biophysics, immunology, microscopy, flow cytometry, transcriptomics, and computational analysis. Many of the authors are based at SciLifeLab, which provided an environment where researchers from these different fields could collaborate closely.
“We immensely benefited from several SciLifeLab-supported infrastructures and facilities. For example, the support of the Advanced Light Microscopy facility and the National Microscopy Infrastructure was key for our project,” says Luca Andronico, the first author of the study.
Sezgin’s laboratory of Cell Signaling, Immunity and Nanoimaging (CSI: Nano) is interested in understanding how the physical properties of cells shape their biological function. Over the last decade, many studies have shown that cell membranes are active regulators of signaling, communication, and immune responses, rather than simply passive barriers. However, most of this work has been performed using microscopy on relatively small numbers of cells.
“We wanted to understand whether membrane properties could provide a completely new way of defining immune cell states, similar to how surface markers and gene expression are currently used. It was perfectly timely to ask this question because recent advances in fluorescent probes made it possible to measure such physical properties in high throughput,” says SciLifeLab Fellow alumni and KI researcher Erdinc Sezgin.
The key question was simple: can the physical state of a cell membrane tell us something important about what that cell does?
“The answer turned out to be yes, and we were excited to see that membrane fluidity could reveal functional differences that are not easily captured by conventional markers alone,” Andronico says.
A different way to distinguish immune cells
One of the most exciting moments came when the researchers sorted natural killer (NK) cells solely based on membrane fluidity.
Erdinc Sezgin says:
“One of the most exciting moments came when we sorted natural killer (NK) cells solely based on membrane fluidity, without using any of the traditional markers that are typically employed to distinguish functional cell subsets. The biophysically sorted cells behaved very differently. Cells with lower membrane order migrated faster, while cells with higher membrane order were more efficient at killing tumor cells.”
The authors also applied new technologies such as Pixelgen’s Protein Network Assay, developed by the Stockholm-based company, to understand the molecular differences between biophysically different cells.
Andronico says:
“Cells that looked very similar when analyzed using conventional markers could be distinguished once this biophysical parameter was included. This suggested that we were uncovering a previously hidden layer of immune-cell diversity.”
For decades, immune cells have mainly been classified by the molecules they express on their surface. This study shows that the physical properties of the cell membrane add another layer of information. By measuring these properties, researchers can identify immune cell states that were previously hidden and gain new insights into how the immune system functions in health and disease.
“The next step will be to measure several other biophysical properties simultaneously. Eventually, we would like to answer the question: what makes a good immune cell and how we can make one,” Sezgin says.
