Microfluidic droplets to interrogate single-cell immune communication
Bart Tiemeijer defended his thesis at the Department of Biomedical Engineering on September 8th.
For his research, Bart Tiemeijer developed a platform to investigate two different types of immune cells at the level of a single cell. He did this by encapsulating the cells in miniscule "microfluidic" droplets. This was done to investigate macrophage interactions on pathogen signals, and to study the interaction between T cells and antigen presenting cells. In this process, he discovered a special population of macrophages that secretes both inflammatory and anti-inflammatory signals in response to bacterial signals.
To protect our bodies, the immune system has evolved into a complex collaboration of cell populations, in which each cell type has its own function. The vast majority of research on this, was done in experiments looking at the population as a whole. The contribution of each individual cell was then often overlooked. Therefore, the different functions as performed by different immune cells are best compared to occupations. Everyone knows the occupational description of a painter; applying paint to a house with a brush. But when a group of painters is commissioned to paint a house, what is everyone's individual role in this? Do all the painters start painting at the same time? Do they all paint at the same speed? Or is there perhaps one painter among them who encourages the rest of the group to paint faster or slower? This variation in performing a function is called heterogeneity.
Through new technologies, which measure the activity of individual cells, such heterogeneity can be studied within populations of immune cells. To achieve this, cells are captured one by one in so-called microfluidic droplets, completely isolating them from each other. This is best compared to painters who are each given their own little house to paint.
With such methods, we can study whether all immune cells in a population respond the same to an outside stimulus, and what the role in this is of intercellular communication. This is heartbreakingly important because today we are working hard to develop immune therapies. Such therapies attempt to strengthen the immune system and help eliminate threats. So for therapies to be as effective as possible, it is important to know whether we should target them to that one painter who paints extra fast, or know how to motivate other painters.
One such cell type that shows a lot of heterogeneity is the macrophage. This is an important immune cell in the early phase of infection. Macrophages are present in almost every tissue of the body and when they detect a potential threat, they activate each other and other immune cells using signaling molecules. In this study, Tiemeijer applied the technique that captures cells in droplets to examine macrophages. This allowed him to activate macrophages at the level of a single cell and study the heterogeneity with which they respond. This showed that when individual macrophages detect a bacterial infection, they do not simply emit an inflammatory signal promoting clearance of the bacteria. There is also a small population of cells (about 10%) that actually emit an anti-inflammatory signal. Such a population thus likely plays an important role in the course of inflammatory responses, and thus may be an important target for immunotherapy.
T cells are "the killers" of our immune system and are capable of detecting and specifically eliminating diseased cells. Before they can do this, they must be activated by a physical interaction with an antigen-presenting cell (APC). Once such a "handshake" has successfully occurred, the T cell will be activated, start to multiply and actively detect and eliminate diseased cells. The effectiveness of this process depends entirely on that one interaction between an APC and T cell. To investigate this interaction in an isolated environment, i.e. without signals from other cells, Tiemeijer also captured these cells one-to-one in microfluidic droplets. Through this approach an objective comparison could be made in the potential of each individual T-cell to protect our body.
Title of PhD thesis: “Microfluidic droplets to interrogate single-cell immune communication”
Supervisors: Jurjen Tel, Anthal Smits and Carlijn Bouten