Throughout National Diabetes Month, we will be sharing developments into Joslin’s unique approach for a permanent cure for type 1 diabetes. Our mission is to prevent, treat and cure diabetes so that one day there will be a world free of diabetes and its complications.
In type 1 diabetes, immune cells called T cells destroy insulin-producing pancreatic beta cells. Scientists have known about this autoimmune attack for decades, but they are still grappling with its wildly complicated details.
Thomas Serwold, Ph.D., who is part of Joslin’s Immunobiology research section, answers questions about his lab’s work and the overall progress in understanding autoimmunity.
Do you have a favorite metaphor for how T cells work?
One is that T cells are like police detectives, and every cell is like a house. The police drive down the street and they look at every house as they drive by. And they try to say, okay, is there something going on in that house that I don’t like?
Police driving down the street look for tell-tale signs of criminal activity. T cells have a similar way of figuring this out.
What they do, and what police also can do, is look through the debris that each ‘house’ continuously produces, because that trash tells you a lot about what’s going on inside. If people have guns or drugs, for example, there will be some remnants of those activities in the debris that those people leave behind.
Cells also are producing debris in the form of chopped-up protein fragments.
Cells recycle their proteins continuously. Many of the proteins don’t fold properly or are specifically degraded during cellular activities. Such proteins get chopped up into peptides (small protein fragments) and a lot of those fragments get transferred from inside the cell out to the cell surface, where they are put on display so that T cells can inspect them.
Since the protein fragments displayed on the cell surface come from proteins inside the cell, they tell a lot about what that cell is up to. If that cell is infected with a virus, for example, there will be fragments of virus proteins on the cell surface. T cells that recognize those virus protein fragments can recognize and kill such infected cells. So, by snooping through cellular debris, T cells find and eliminate cells infected with pathogens.
It’s a lot like CSI.
The TV crime drama?
What happens in an autoimmune reaction?
In autoimmunity, some T cells mistakenly recognize and become activated by fragments of normal cellular proteins. In the case of type 1 diabetes, some T cells bind to protein fragments from insulin-producing cells. This leads them to attack and kill the insulin-producing cells just as if those cells were infected with a virus.
How do T cells recognize the “debris”?
T cells have specific receptors on their surface that can bind to these short protein fragments. These receptors are special, because they are generated when T cells develop within the thymus, through a modular assembly process that uses randomly selected receptor modules. This process randomly generates a unique receptor that can bind only to certain pathogen-derived protein fragments.
That’s the power of the adaptive immune system—billions of T cells all have their own unique receptors, so we can recognize almost any pathogen that ever infects us. But the danger there is the potential for autoimmunity.
Where does autoimmunity begin?
There are many different levels of T cell tolerance to the body’s tissues, and places where it can go wrong.
One place where it can go wrong is in the thymus—the organ where T cells develop. Here, when T cells generate their unique receptor, they test it out to make sure it doesn’t bind to any of the body’s own protein fragments—for example, a T cell with a receptor that binds to an insulin peptide would be screened in the thymus and eliminated.
However, this process doesn’t work perfectly. If enough of potentially autoimmune T cells survive their development within the thymus, the chances of getting autoimmune disease will increase.
What does your lab study?
Our major project right now is to try to understand the cells that help T cells to develop, and whether these cells can be altered to prevent autoimmune T cells from developing in the first place.
T cells are produced in the thymus throughout life. When T cells generate their unique T cell receptor, they test its functionality with the help of epithelial cells that reside permanently within the thymus. Epithelial cells within the thymus there are like teacher cells, and one of their essential jobs is to prevent T cells that might be autoimmune from graduating and leaving the thymus, where they might cause disease.
These cells have an enormous impact on the ability of T cells to mature and function properly. Developing techniques to manipulate the functions of these cells through genetic modification and epithelial stem cell transplantation will tell us a lot about how the autoimmune T cells that drive type 1 diabetes come to develop, and how they might be eliminated.
In another project, we’re trying to understand what drives the growth of developing T cells. We think that in the thymus, there’s sort of a balance of biochemical signals from outside the T cells. There are some signals that drive T cell proliferation and some signals that drive cell death. But we’ve found a line of mice that seem to have a misbalance in these signaling pathways that drive cell proliferation. We’re seeing if that might predispose the cells in those thymuses to autoimmunity.
How much progress is the field making in discovering how to stop the type 1 autoimmune attack?
Once you have an ongoing immune response, you have so many T cells that are reactive to your body—it is a big challenge to specifically inactivate the bad T cells without also eliminating the beneficial T cells.
That being said, we now know that the immune system has built-in mechanisms that shut down T cell responses, and keep them from getting out of control. Discoveries in this area of research have been providing new ideas for how we might enhance our normal mechanisms for stopping autoimmunity. Some of these ideas are already being tested in clinical trials, and more are certain to come. So I am excited about the progress being made.
Also, I think that we are still in the discovery phase of this disease. We have identified many, but certainly not all, of the important cell types and proteins that are involved, and we are still trying to figure out how these parts fit together and interact, both with one another and with the environment, to drive the immune disease. There is a lot of progress being made. As this picture becomes clearer, our ideas and our attempts to stop the autoimmune attack will improve.
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