A fully functioning immune system is dependent on good communication between many different types of cell. We know that one set of cells detects damage and infection, while another leaps into action to defend the body. But we weren’t entirely clear how the two ‘talked’ to each other. In this blog, Prof David Jackson and his senior post-Doctoral fellow Dr Louise Johnson explain the team’s newest finding, which suggests that a special type of carbohydrate acts as the broker between the two.
Our immune system helps us fight off infections – from the common cold to more serious, life threatening diseases. To accomplish this, patrolling white cells, specialised in detecting microorganisms, rush to the site of initial attack to provide immediate early protection. Soon afterwards, these “lookouts” communicate the details of any infection to lymphocytes. Lymphocytes are the heavy hitting immune defence population that resides in our lymph glands, telling them to increase their numbers and go to war against the invaders. To convey this vital information, the patrolling white cells first have to enter the lymphatic system – a pipe-like network akin to the blood circulation that opens into the lymph nodes, but which carries tissue fluids rather than oxygenated blood. Exactly how white cells crawl into lymphatic vessels has remained largely unknown up till now, but our recent research has revealed an unlikely connection with a large sugar-like molecule present throughout the body called hyaluronan.
This slimy, jelly like carbohydrate acts as a space-filling substance, and the skin is full of it. In fact hyaluronan is so important that embryos lacking it don’t survive. Surprisingly, this vital compound is now a key ingredient of commercial skin moisturisers and beauty products sold in high street chemists. But how can sugary slime help cells switch on the immune system? The answer lies in the fact that hyaluronan forms a surface camouflage around white blood cells that allows them to move freely within the skin without getting stuck. Although neighbouring skin cells they come up against have sensors for hyaluronan, these are occupied by resident skin hyaluronan so the white cells can easily move on by.
Our work shows that lymphatic vessels are covered with a distinct form of hyaluronan sensor called LYVE-1. LYVE-1 detects the white cell hyaluronan cloak through weak electrostatic attraction. In this case it tells the white cells to “come on in”. Amazingly, when we viewed events using high powered microscopes we could see that contact between white cells and the outer surface of the lymphatic vessel caused the latter to form LYVE-1 coated tentacles that wrapped themselves around the white cells, pulling them through to the vessel interior. We know this curious sequence of events is really important, because if we switch off the gene that makes LYVE-1 or interfere with the hyaluronan cloak, white cells can no longer enter the lymphatic system and navigate to the lymph nodes.
But it doesn’t stop there – LYVE-1 lines the interior of the lymphatic vessels as well as their outer surface. There, we strongly suspect it helps white cells inside the lymphatics to crawl the relatively long distances to lymph nodes and subsequently meet up with lymphocytes to kick off immune responses. The more we understand these intricate mechanisms that control immune responses, the more likely we will be able to harness them for delivering protective vaccines on the one hand or for preventing destructive immune responses on the other.