02 Jan 2013, BioSpectrum Bureau , BioSpectrum
Singapore: A study led by researchers at the Columbia University Medical Center (CUMC) found that the immune system mounts a surprisingly robust anti-inflammatory T cell response in reaction to the development of atherosclerotic lesions, which helps prevent the disease from progressing. The findings may help in designing anti-atherosclerosis vaccines and other therapies.
When the body encounters viruses, bacteria or other potential threats, dendritic cells, which are the sentinels of the immune system, are dispatched to take a sample of the pathogen and present it to T cells. This activates the production of pro-inflammatory effector T cells that attack the pathogen and anti-inflammatory regulatory T cells that keep the pro-inflammatory response in check.
"Normally, the pro-inflammatory response dominates, and that is what people assumed to be the case in atherosclerosis," said study leader Dr Ira Tabas, Department of Medicine, and professor of pathology and cell biology in physiology and cellular biophysics at CUMC. "However, we found that the T cell response to atherosclerosis is mostly anti-inflammatory."
The researchers led by postdoctoral scientist Dr Manikandan Subramanian, used mice whose dendritic cells lacked MYD88, a signaling protein that initiates the cells' maturation. Since immature dendritic cells cannot activate T cells, the elimination of MYD88 effectively disabled the production of both effector and regulatory T cells. The mice were also bred to lack the LDL receptor, leaving them prone to the development of atherosclerosis.
The net effect of these changes in the mice led to increase in the size of atherosclerotic lesions. "What this means is that the dominant effect of dendritic cells in the setting of atherosclerosis is to promote the development of protective regulatory T cells," said Dr Tabas.
Earlier studies suggested just the opposite, that effector T cells dominate in response to atherosclerosis. "In those studies researchers disabled dendritic cells at an earlier stage, creating all sorts of compensatory processes," said Dr Tabas. "That's probably why they came to a different conclusion. In our model, we were able to knock out only the step involved in activating T cells, leaving everything else alone."
The researchers found that T regulatory cells act by suppressing pro-inflammatory effector T cells and macrophages, which was expected. They also identified a new mechanism that directly links regulatory-T-cell activation with protection from atherosclerosis. According to Dr Tabas, regulatory T cells secrete TGF-beta (a cytokine, or signaling molecule), which suppresses MCP-1 (monocyte chemoattractant protein-1), a protein that recruits monocytes, a type of white blood cell.