The cells of the immune system protect the body against various pathogens such as bacteria, viruses and fungal agents. To do this, they carry an arsenal of molecules and enzymes designed to fight these pathogenic micro-organisms. Among the most active enzymes are the proteases, which digest the proteins in the micro-organisms, killing them or destroying their toxins.
The proteases in immune cells, however, are like a double-edged sword as they can also damage the cells that carry them. For this reason, they are kept compartmentalised in vesicles inside the cells, which only release their contents when facing a threat.
By studying a family of molecules contained in the immune cells, the research group led by Prof. Dr med. vet. Charaf Benarafa has discovered the role of a second layer of protection against these powerful proteases: the serpin family. The serpins (an acronym derived from serine protease inhibitors) protect the body’s cells against their own internal weapons.
Nathan Leborgne’s thesis showed that serpins also play a key role in the regulation of inflammatory processes independent of cell death and opened up new avenues for research into the regulation of the body’s response to infection.
Interview with Dr Nathan Leborgne about his thesis on serpins – the safety backstop of the immune defence system
What was the aim of your thesis?
My thesis aimed to study the role of two members of the serpin family – serpin b1 and serpin b6 – in the inflammatory and survival mechanisms of two populations of immune cells. The two types of immune cell we chose were neutrophils and NKT (Natural Killer T-cell) lymphocytes, as these cells are crucial in the body’s defences against bacterial infections. In the case of neutrophils, a further aim was to identify the set of molecules targeted by *cathepsin G, one of the most important proteases in the neutrophil armament, whose action is inhibited by serpin b1 and serpin b6.
What are the main results of your thesis?
Using a new *proteomics technique called Terminal Amine Isotopic Labelling of Substrates or “TAILS”, I was able to identify 91 potential targets of cathepsin G in neutrophils, each of which is potentially involved in the neutrophil’s inflammatory and survival mechanisms. I also showed that serpin b1a expressed in the mouse and the homologue of the human gene was not indispensable in NKT cell biology. I found that the development and immune activity of these cells, and more specifically their pro-inflammatory *cytokine expression, were not regulated by serpins.
How will your results help to advance research?
Identifying new substrates of cathepsin G opens up new avenues for research. The targets involved in neutrophil cell survival or inflammation may enable us in the long term to treat diseases in which neutrophil activity is harmful to the body, such as atherosclerosis or chronic obstructive pulmonary disease. The results observed in NKT lymphocytes alert the scientific community to the need to study the biology of these cells further by analysing the influence of molecules other than serpin b1.
What are you most proud of in this work?
Embarking on a thesis forces you to query a lot of things. You come across plenty of technical and methodological problems and often doubt your own ability to complete the project successfully. I am proud that I persevered and saw this work through.
What did you especially like about undertaking your thesis?
The contact and interaction with other people working at the IVI. Especially my supervisor, Professor Charaf Benarafa, but also the other students, technicians, instructors and other IVI staff. I learned a lot from them.
What was your time at the IVI like?
My four years at the IVI went by in a flash. I really enjoyed the atmosphere in our group, which was both relaxed and able to work hard and deliver.
What projects do you have coming up, what are your plans?
My aim is to continue in scientific research and pursue an academic career. I am currently finishing a project following on from the cathepsin G results in the same group, which I hope to publish soon. Then I plan to take a post-doctorate abroad in the field of protease immunology. In the meantime, I’d also like to spend a few weeks travelling if the health situation allows.
*cathepsin G: a member of the protease family of proteins with the ability to catalyse other proteins, breaking them down into smaller fragments and thus destroying attacking pathogens. This ability can also be dangerous for the host cell, hence the need to store proteases in vesicles.
*proteomics technique: a molecular biology technique used to study the proteome, i.e. the complete set of proteins in an organism.
*cytokine: a molecule that regulates inflammation. Cytokines are expressed by various cells in the body. They serve as messengers for the immune system cells, controlling their activity and function.