Diabetes 101: thymic selection part 1

July 14, 9:00 AMDiabetes ExaminerRobert Scheinman

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A T cell responds to a presented antigen.

Type I diabetes occurs because of things which happen at the beginning; the time during which the fetal immune system begins to take its form. To understand why some people get this disease, then, we need to go back to that time. Baby T cells are called thymocytes and they grow up in (you guessed it) the thymus. When T cells grow up their job will be to look at antigens and determine if they are dangerous. For the purposes of this article let’s consider antigens to be little pieces of proteins – approximately 10 amino acids long (to read up on antigens and how they are presented click here). If a T cell decides that indeed an antigen is dangerous, it will activate and begin to divide to create many clones of itself (an army of one). This army can do a variety of things such as convince B cells to make antibodies, secrete factors to rev up macrophages and other killers, or it can just decide to do the killing itself. We might call the collection of all antigens that the immune system can see its “repertoire”. The weirdness comes in when one begins to understand the process by which this repertoire is sculpted.

T cells see antigen through the T cell receptor. Like all other receptors it works via a lock and key sort of mechanism. In other words, the antigen must be perfectly shaped to fit into the binding pocket of the receptor like a key in a lock. Now each T cell has a unique T cell receptor that arises from a random mixing and matching of bits of chromosome (to read more about the T cell receptor and how it arises from recombination click here). Many of the T cell receptors that arise from this process of recombination are totally useless. Thus one of the goals of the immune sculptor is to remove those T cells that do not contribute to the repertoire. Another is to remove T cells that are likely to cause autoimmune disease. These processes which sculpt the T cell repertoire into its final shape are collectively called "selection".

So it appears that the antigens themselves act as the sculptors in that it is the reaction of the T cell to the antigens set before it that sets its fate in motion. The critical point comes from the realization as to where these antigens come from. There are no infections at this early time and nothing foreign is available. All of these antigens are actually bits of self; bits of our own genes, translated into proteins, chopped up, and presented buffet style to the waiting line of hungry thymocytes. If, after all of this varied buffet, the T cell has not responded  - it dies. It actually commits cellular suicide, releasing a host of enzymes within itself to kill itself from the inside. Macrophages within the thymus engulf the debris. Now, importantly, if the T cell responds exuberantly in response to a bit of self, it is likely to cause autoimmune disease. Again, those suicide enzymes are activated and the cell dies. This is called negative selection. This is a really strange way to set up the immune system as it means that all surviving thymocytes must be and indeed are self reactive. Each and every T cell that survives this deadly course of thymic education has the capacity to turn upon us and devour us. A sobering thought.

In the next part of this article we will consider how thymic selection contributes to type 1 diabetes.