MS Society-funded postdoctoral fellow identifies a molecular switch that restrains the development of inflammatory immune cells
Multiple sclerosis is an autoimmune disorder that occurs when immune cells target and attack the central nervous system (CNS), causing inflammation and damage to both myelin (the protective covering around nerve fibers) and, eventually, nerve fibers as well. A leading agent in this inflammatory attack is a type of T cell called Th17. Present at sites of CNS inflammation, Th17 cells are capable of releasing pro-inflammatory molecules, as well as recruiting other inflammatory immune cells that cause damage to the myelin and nerve fibres.
Th17 immune cells are not always inflammatory and disease-causing (in other words, pathogenic). Many are beneficial, involved in keeping the gut’s microbes in check or defending the body against possible fungal or bacterial infections. These Th17 immune cells exist in a non-pathogenic state, providing the necessary protection we expect from our immune system. The mechanisms that can switch Th17 cells to act as either pathogenic or non-pathogenic are not well understood.
To address this question, MS Society-funded postdoctoral fellow Dr. Chao Wang from Harvard Medical School and a team of researchers set out to identify molecules unique to either pathogenic (harmful) or non-pathogenic (helpful) Th17 cells. They discovered a protein called CD5L, which acts as a molecular “switch” that can help to restrain the cell’s pathogenic development. Their findings were recently published in the prestigious journal Cell.
The researchers analyzed the genetic “blueprints” of both pathogenic and non-pathogenic Th17 cells grown in cell culture, as well as Th17 cells taken directly from mice with an MS-like disease. They were able to identify a gene that codes for a protein called CD5L – this gene appeared when Th17 cells were in a non-pathogenic state and was absent when the cells were pathogenic.
They next tested how experimentally switching off CD5L would affect the behaviour of Th17 cells. This was accomplished using a series of experiments in cell culture as well as in genetically modified mice (transgenic mice) in which CD5L was genetically removed.
The researchers also induced an MS-like disease in these same transgenic mice. The team was then able to assess how loss of CD5L affected the animals’ clinical symptoms (hind limb and tail paralysis, which are a measure of disability of animals with MS-like disease), as well as Th17 cell behaviour in an immune system primed to be aggressive.
Prior research has already established a role for CD5L in regulating fatty acid metabolism in the body’s fat storing cells (called adipocytes). Based on this knowledge, the research team hypothesized that CD5L could control Th17 cell behaviour by altering its fatty acid profile. The authors compared and contrasted the fatty acid content of Th17 cells when CD5L was either present or absent, with a particular focus on saturated and polyunsaturated fatty acids. They also examined how CD5L affected the synthesis of cholesterol in Th17 cells.
A final set of experiments tested whether alterations made to either fatty acids or cholesterol synthesis could affect a well-known master regulator of Th17 cell development, the protein Rorγt.
CD5L was abundant in non-pathogenic Th17 cells only; it was almost completely absent from pathogenic Th17 cells. When CD5L was genetically switched off, mice with an MS-like disease developed more severe symptoms of disability. With CD5L absent, the balance between pathogenic and non-pathogenic Th17 cells shifted to favour a pro-inflammatory state.
At the molecular level, CD5L controlled Th17 function by altering the cell’s fatty acid composition and restricting cholesterol synthesis. With CD5L gone, saturated fatty acids and molecules derived from cholesterol became more abundant. These molecules then instructed the cell’s master regulating protein, Rorγt, to shift the Th17 cell towards the pathogenic form.
When CD5L was present, Th17 cells produced higher levels of polyunsaturated fatty acids, while limiting both saturated fatty acid levels and cholesterol synthesis. Polyunsaturated fatty acids then directed the regulator protein Rorγt to maintain Th17 cells in a non-pathogenic state, promoting the generation of anti-inflammatory molecules.
The authors singled out CD5L as a molecular switch that controls the balance between helpful and harmful TH17 immune cells. In non-pathogenic Th17 cells, CD5L acts as a restraint, limiting possible Th17 aggressiveness. When CD5L is lost, non-pathogenic Th17 cells convert to become inflammatory and pathogenic.
At a molecular level, CD5L functions by altering fatty acid composition (more polyunsaturated and less saturated fatty acids) while also restricting cholesterol synthesis. This delicate balance in fatty acid composition controls how the cell response to Rorγt, a master regulator that affects TH17 cell development.
The external factors that control the levels of CD5L in TH17 cells are still very much a mystery? However, the researchers suggest looking to the gut for answers, as the tissue in the intestines is rich in non-pathogenic Th17 immune cells. In fact, the interaction between the so-called “gut microbiome” – the extensive community of microbes living in the gut – and the immune system is an emerging topic in MS research today. Understanding how CD5L levels are maintained in this environment, as well as what signals are important to CD5L’s regulation, will no doubt form the basis of future research.
Wang C et al. (2015). CD5L/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell. In Press.
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