Another target of autoreactive T cells: defective protein production
by Adam Burrack, PhD
One reason insulin may become a target of autoreactive T cells is because it is associated with inflammation in the pancreas. As I’ve previously described, inflammation is one signal T cells that from their environment which indicates that it’s time to respond to a threat (like a virus or bacteria). Another signal that helps to “activate” T cells to respond to threats are new peptide targets. Normally, T cells that have the potential to cause autoimmune disease are deleted in the thymus during development. In a system where these cells weren’t purged, humans would develop multiple types of autoimmunity at very young ages. In fact, the safe-guard goes a full step further. T cells which have moderately strong reactivity to self (think of it as a spectrum of strength of response) are not deleted, but rather are diverted into a different lineage of cells called regulatory T cells. The sole purpose of this sub-set of T cells is to prevent autoimmunity during times of inflammation and moderate organ and tissue damage. For example, part of the training response to exercise involves moderate amounts of muscle damage – even the release of some damaged proteins – so that the muscles can respond to the stress and become stronger. If we did not have regulatory T cells – as well as different ‘flavors’ of inflammation, the type of inflammation associated with exercise (mediate by the cytokine IL-6) is slightly different than the type of inflammation resulting from viral infection (mediated by type 1 interferon) – we would develop autoimmunity to our own tissues. Therefore, very few – if any – T cells with the potential to cause autoreactivity make it into the circulation of a normal adult human. So the question remains: how does autoimmunity develop?
One answer is genetic susceptibility. For unknown reasons, individuals with certain gene types related to how T cells are activated develop autoimmunity – including type 1 diabetes – more frequently than other individuals. A second answer is slight perturbations in T cell development. For reasons that are not completely clear, individuals with the propensity to develop autoimmunity seem to have a higher-than-normal number of autoreactive T cells. This likely has something to do with how T cells develop in the thymus, but is not understood well enough by basic science researchers in order to manipulate it to prevent autoimmunity. A third answer might be gut microbiome. Emerging evidence has begun to suggest that a more narrow range of bacteria in the gut is associated with autoimmunity, including type 1 diabetes. Whether this is cause, effect, or unrelated to disease onset is not clear at this time.
A fourth potential answer is the development of new peptides associated with beta cell destruction, to which there are no pre-existing T cells. In this case, there would be no regulatory T cells to prevent attack, and there would have been no selection in the thymus during T cell development against the survival of T cells responding to these peptides. From the perspective of the T cells, they would be doing what they should: attacking the source of a new peptide that is associated with inflammation. This is how the immune system has evolved to operate in mammals. The recent observations of hybrid peptides, which contain one portion of the insulin molecule and a second portion from a different protein found in the insulin secretory granule was the first demonstration of this principle in type 1 diabetes.
Today’s article establishes a second example of this “new peptide” explanation for the origins of autoimmunity. In a recent article in the journal Nature Medicine from Bart Roep’s group at City of Hope in Los Angeles, researchers characterized a ‘defective ribosomal insulin gene product’ as a target of both CD4 T cells and CD8 T cells. What this means in English (or at least non-basic science-speak) is the following. When beta cells are stressed out by inflammation and high-demand for insulin production (as in when neighboring insulin molecules are getting killed and there is more demand for each remaining beta cell to produce more-and-more insulin), sometimes the production of insulin gets screwed up in the rush to keep up. This ‘screwed-up’ insulin could then be seen as a ‘new protein’ being produced by cells under the attack. These cells under attack could then be mistaken by the immune system, logically enough, as infected with a bacteria or virus. The immune system then re-doubles its efforts to eradicate the cells responsible for production of this foreign peptide.
From the perspective of the beta cell, that sucks. You’re doing job as best as you can, a couple mistakes get made along the way because you’re just that busy, and that gets you killed – and your neighboring beta cells killed – even faster. From the perspective of the immune system, job well done. And not only that, but memory T cells will be developed against this mis-made insulin target. So that if an insulin-producing transplant is ever performed, the T cells will remember that weird-insulin target.
The good news is, having discovered this basic principal that T cells appear to really be doing their job quite well when they are destroying beta cells, researchers can now begin to think about ways to leverage these ‘new targets’ in attempts to re-create immune tolerance to insulin-producing transplanted cells. Understanding what the targets of autoreactive T cells are – especially the ‘new targets’ like hybrid peptides and defective ribosomal products – gives researchers rational approaches to try to reverse autoimmunity. Most likely this will require a two-step process: (1) get rid of the memory autoreactive T cells (using as-yet-to-be-invented technology), (2) induce immune tolerance to ‘new targetes’ (using unknown future method). So as a reality check, the strategy is clear, the methods; however, are not.