The immune system plays a vital role in heart disease. In my last blog, I wrote about the role of complements in hypertension and lightly mentioned that it affected regulatory T cells. In this post, I would like to shine the spotlight on regulatory T cells, their function and their role in atherosclerosis, drawing attention to a recent publication that describes how the different forms of the RNA material in these cells correlates to cardiac incidents.
Regulatory T cells, or commonly known as Treg cells, belong to the T cell family, a part of the adaptive immune system. Treg cells play an important role in reducing inflammation and keeping the immune system in check. They are involved in multiple inflammatory diseases and their presence is crucial for controlling unnecessary immune activation that can lead to disease. Treg cells are protective in multiple heart conditions. Treg cells play a big role in controlling atherosclerosis progression and reducing the inflammation that occurs during plaque build up. Experiments, where researchers got rid of Treg cells, exacerbate atherosclerosis. Meanwhile transferring Treg cells into animals, reduce the severity of atherosclerosis. In addition to reducing inflammation, Treg cells also play a role in tissue repair as well as modulating lipoprotein metabolism. Reduction in Treg cells have been shown to correlate with increased risk for myocardial infarction and their numbers are either reduced or they switch to other inflammatory T cells in atherosclerotic lesions.
Treg cells function is dependent on their master transcription factor and regulator, Foxp3. Foxp3 is also the main molecule that defines these cells from other T cells. While only one form of transcribed Foxp3 mRNA is found in mouse cells, in humans, Foxp3 mRNA exists in more than one isoform. The two most dominant isoforms are the full length Foxp3 mRNA (foxp3fl) and a truncated form lacking exon 2 (foxp3Δ2). In a recent research article published in Circulation Research, a group of researchers from Karolinska Insitute in Sweden, examined the role of these two isoforms on Treg cells function and whether their presence correlated with disease incidents. The researchers first found that the activation of Treg cells resulted in more expression of the truncated isoform of foxp3. When they examined patients with atherosclerosis, the researchers found that patients who had unstable plaques; those defined as having one or more cardiac incidents; had lower expression of the truncated isoform of Foxp3 despite the fact that the total mRNA levels of Foxp3 was the same. This suggested that the Treg cells that express this truncated form are more protective against atherosclerosis.
This new research is very interesting and leads to many questions in the field. Does the same hold true with other cardiac disease like myocardial infarction? Can manipulating the Treg cells by expressing only the truncated isoform of Foxp3 reduce cardiac incidents? The researchers found that the truncated isoform of Foxp3 induced a specific glycoprotein that tethered TGFβ, an inhibitory cytokine, to the membrane of Treg cells. If this tethering were achieved differently, would it lead to the same results? There are still a lot more questions to be answered but the current research definitely points to the idea that it is all about form over abundance when it comes to the expression of Foxp3 in Treg cells.
Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development.