Type 1 diabetes is an autoimmune disorder in which the insulin-producing beta cells in the pancreas are killed by the body’s own T cells. How and why T cells attack the beta cells is still up for debate, but it is clear that stopping the T cells from killing the beta cells is an important step in halting the progression of type 1 diabetes. New research out of Professor Len Harrison’s lab published in the journal Nature Immunology has identified a novel mechanism for suppressing T cells that scientists hope could lead to a therapy for autoimmune diseases like type 1 diabetes. The lab of Dr. Harrison at the Walter and Eliza Hall Institute of Medical Research has studied ways to stop the pathogenic cells of the immune system in type 1 diabetes for many years, and they hope that their most recent finding is a step in that direction.
Dr. Harrison and his team identified that some T cells express a molecule on their surfaces, CD52, that is capable of suppressing other T cells. Understanding the ways in which the immune system normally controls and suppresses T cells is crucial to our understanding what goes wrong in autoimmune diseases, and also gives us new tools as we try to treat the incorrectly activated cells we see in type 1 diabetes. Scientists already know about a number of important mechanisms by which the body controls T cells, including receptors like CTLA4 and PD1. These receptors are presented on the outside of T cells, and, if engaged, function to turn off those T cells and keep the immune system in check. CTLA4 and PD1, though, only work for the T cells they are on; an even more powerful control mechanism in the immune system is regulatory T cells. Regulatory T cells (Tregs) are a special type of T cell that can silence other T cells. If T cells are the body’s army, then Tregs are the military police, keeping T cells in line.
So what is CD52, and where does it fit in the body’s toolbox of regulatory mechanisms? CD52 is one of many proteins that can be expressed on the outside of T cells, and prior to this study, nothing much was known about it. In fact, Harrison’s group didn’t start out looking at CD52; they observed that when they made T cell clones that recognized GAD65, one of the self-proteins that T cells aberrantly respond to in type 1 diabetes, one subset of the T cells were activated as expected, but another subset of the T cells seemed to be suppressive, quieting rather than inflaming nearby cells. The researchers therefore compared the set of proteins on the outside of the nonsuppressive and suppressive cells, and they found that a high level of CD52 was the most reliable differentiator between the two subgroups.
Looking more closely at these cells with lots of CD52, the researchers found first that they didn’t look like traditional Tregs, as they lacked the cellular markers that those cells carry. However, the CD52-high cells behaved similarly to regulatory T cells: not only did the cells themselves produce less of inflammatory chemicals, but they decreased the activity of nearby CD52-low T cells. This suppressive activity was seen even when the CD52-high cells didn’t touch the other cells, implying they were releasing a suppressive chemical signal. Further, using a mouse model of type 1 diabetes, the researchers found that depleting normal T cells of the CD52-high group led to significantly faster disease progression.
CD52-high cells, then, seem to be a suppressive subset, but what does this mean for type 1 diabetes in people? There is some evidence that Tregs are deficient in people with type 1 diabetes, and scientists hypothesize that these deficiencies lead to a breakdown in regulation that allows autoimmunity to progress. Dr. Harrison, however, believes that Tregs must be only part of the story; the deficiencies in Tregs in diabetics have thus far been found largely in the periphery, among circulating Tregs, but type 1 diabetes is a tissue-specific disease. Dr. Harrison therefore hypothesizes that some part of the breakdown in regulation must be coming from tissue-specific cells, rather than just a general Treg problem, and the CD52-high subset of cells that his group found may be the set of tissue-specific regulatory cells he is looking for. The researchers extracted T cells from patients at risk for type 1 diabetes who were antibody positive, patients with type 1 diabetes, and matched controls (with 14 people in each category).
When the researchers expanded the T cell population that recognized the type 1 diabetes-associated antigen GAD65, they found that the at-risk and type 1 diabetic cohorts had fewer CD52-high T cells than the controls. This difference was specific to GAD65, as T cells that recognized a control antigen were not different between the cohorts. What this implies is that type 1 diabetics might generate fewer of these CD52-high suppressive cells in response to particular stimuli. So, to put it all together, you can imagine that T cells begin to get activated around beta cells, perhaps in response to illness or other natural causes, and in patients susceptible to type 1 diabetes, suppressive T cells that should be created to quiet the activated T cells are not created. This lack of suppression around the beta cells gets out of hand, and pretty soon you have a full-blown, tissue-specific autoimmune reaction that kills off the beta cells.
This is all conjecture at this stage, but whether or not a deficiency of CD52-high cells is involved in the development of diabetes, Dr. Harrison’s group goes on to show that CD52 itself might have a role to play in treating diabetes. The researchers conducted a series of experiments that showed that it was CD52 itself that had suppressive effect on T cells, and that the protein CD52 alone could block the activation and proliferation of T cells by binding to an inhibitory receptor on the outside of those cells called Siglec-10.
The obvious next question is– can CD52 prevent the T cells around the pancreas from starting their autoimmune cascade? Unfortunately, we will have to wait for that answer, even in mouse models; Dr. Harrison’s group has begun that research, and is very excited about the results, but can’t say anything while they await the publication of their next paper on the topic. Dr. Harrison is optimistic, though, that CD52 could be made into a drug to be tested in a number of immune conditions including type 1 diabetes and other autoimmune diseases such as multiple sclerosis.
What does this mean for you and me, as people with diabetes? As always, don’t hold your breath. Still, this is an exciting early finding of a new molecule that we can add to our immunomodulatory toolbox. CTLA4, anti-CD3, and more recently live Tregs are some of the other tools in that toolbox, and each adds to our understanding of the disease and our understanding of what we need to do to prevent it from progressing if caught at an early stage. Many of the top names in the field* are now positing that a single treatment will not be enough, and that we will need a cocktail of immunomodulatory agents to deal with each of the complex components of the autoimmune reaction. Dr. Harrison here has pointed us in the direction of a new mechanism relevant to type 1 diabetes, and further to a potential way to tip the immune balance back in favor of suppression.
For more about Len Harrison’s work see Can A Vaccine Prevent Type 1 Diabetes?