Speaker: Michael Sixt (Group leader & vice president IST Austria)
Subject: Molecular Control of Leukocyte Chemotaxis
Location: Erasmus Medical Center Rotterdam
Date: Monday, March 16 16:00-17:00
Author: Jasper Veerman
While many researchers in his field study several properties of the immune system to better understand it, Michael Sixt uses the immune system of mice as a model to study his primary interest: cell movement. Leukocytes, also known as white blood cells, are very dynamic cells that move through lymphatic vessels upon activation (for example skin damage). They migrate to a location called the lymphatic node, where they present the antigen they captured. In doing so, many movement-related challenges are to be overcome. Below, I will discuss the first challenge of the migration of the activated leukocyte into the lymph vessel.
Since cells are “blind”, they need special cues to travel to the desired location. Chemotaxis is the process where cells sense increased concentrations of a certain ligand, and therefore move towards or away from this gradient, depending if they are attracted to, or repelled from this substance. The presumed attractor of leukocytes, CCL21, is immobilized around lymph vessels, forming a gradient with increasing concentration from distance onwards. This proposed mechanism was tested – and proven – by destroying this CCL21 gradient, after which the leukocyte no longer moved specifically in the direction of the lymph vessels.
After analyzing the structure of CCL21, it was found to contain a rare C-terminus that could bind to, among others, polysialic acid (PSA). Removal of this recognizing tail resulted in failure of CCL21 to recognize the CCR7 receptor on the surface of the lymph vessel. A likely conclusion is that CCR7 must contain a PSA domain, to which the CCL21 binds. This conclusion was verified experimentally. Furthermore, Michael Sixt’s group is working on finding the molecular details of this binding reaction. The latest model is one in which auto-inhibition plays an important role. Normally, CCL21 has a protecting belt (the rare tail) around the binding site for CCR7. However, when bound to PSA, this belt changes position, allowing proper ligand-receptor binding.