The immune system can be a double-edged sword; we need it to protect us from pathogens and aberrant cells, but if it is not carefully regulated it can cause serious harm to the body as well. When the body encounters a pathogen, inflammatory responses are set in motion. Scientists have now learned more about how immune cells are changed when they respond to a pathogen, and have suggested that this process is linked to aging. The findings, which could help scientists develop better treatments for diseases of aging including cancer and Alzheimer’s, have been reported in eLife.
This study has revealed a cellular process that leads to the formation of protein structures that can come together to amplify signals when an infection is encountered. This amplification can explain how a signal caused by a pathogen can lead to an immune response, even though that signal may be small.
"Like the striking of a match to produce a flame, our immune cells, which are found throughout our body, must undergo a large and irreversible response when encountering a tiny stimulus like a single molecule of viral DNA," explained corresponding study author Randal Halfmann, PhD, an Associate Investigator at the Stowers Institute for Medical Research. "Specific proteins within these cells that can quickly assemble are the death decision makers, and the process of their assembly is the decision for the cell to die. We are beginning to think that this may be one of the fundamental mechanisms of why we age."
The “death decision makers” involve a portion of a protein called a "death fold domain,” which can link together tightly, but in a complex way that would be unlikely to occur accidentally. This linkage is more likely to happen in infected or old cells.
"There are always more than enough of these proteins available to assemble in our cells, which allows the cell to rapidly respond to a threat," said first study author Alex Rodríguez Gama, PhD, a former predoctoral researcher in the Halfmann Lab. "This protein overpacking or 'supersaturation' is biology's equivalent of a battery, storing energy until it is needed to boost a signal that warns the body of an invasion, activating an immune response and inflammation."
This phenomenon can happen in different proteins during the detection of various pathogens. The investigators suggested that death-decision proteins could be self-assembling, since they would otherwise need a lot of energy from the cell.
Additional work revealed a subset of proteins in yeast that carried death fold domains that could power themselves.
While this process can rapidly help eliminate an infection, there are drawbacks. These linkages can also form on their own sometimes, for example. If a cell gets old enough, it will change shape eventually even when it is not infected. This can lead to issues like inflammation and cell death.
"It is a 'Catch-22.' Essentially, we are trading longevity for an immune system, or the greater certainty of life right now at the expense of potential longer life," said Halfmann.
Sources: Stowers Institute for Medical Research, eLife