Self & Other · The Schools of Tolerance
The Word ****“****Mostly****”
This sounds harsh, and it is. About ninety-five percent of young T cells fail this first test. They never had a chance. Their random receptors didn’t fit the basic shape of the body’s MHC. They die in the cortex of the thymus, and you never know they existed.
The five percent that survive have receptors that can at least see the cards. They progress to the second test.
The second test is negative.
In the inner layer of the thymus, called the medulla, the surviving T cells encounter a different population of cells. These cells are doing something almost unbelievable. They are displaying, on their MHC molecules, fragments of proteins from all over the body — not just normal thymus proteins, but proteins from your liver, your pancreas, your brain, your eyes, your skin, your heart. They are showing, in effect, a sample catalog of you.
This is possible because of a single, remarkable gene called AIRE — the autoimmune regulator. AIRE turns on, in these specialized thymic cells, the production of a wide variety of proteins that those cells have no business making, proteins that belong in completely different organs. A thymus cell, thanks to AIRE, will briefly make a fragment of insulin (which belongs in the pancreas), then a fragment of myelin (which belongs around your nerves), then a fragment of thyroglobulin (which belongs in your thyroid), each shoved up onto an MHC molecule for the T cells to inspect. It is as if the school had decided, before letting the students out into the world, to show each one a comprehensive slideshow of every neighborhood in the city, so they would know which faces belong.
Now the second test happens. A surviving young T cell wanders past these displays. If its receptor binds strongly to any of the self-fragments it sees — if it recognizes a piece of insulin, or myelin, or thyroglobulin, or any of thousands of other normal you-proteins — it has just identified itself as dangerous. A T cell that responds strongly to a normal you-protein would, if released, attack your own tissue.
So that T cell is told to die.
It dies. The macrophages clean up.
This is called negative selection, and it eliminates the great majority of self-reactive T cells. By the time a T cell finally graduates from the thymus and enters the bloodstream, it has been positively selected (it can read the cards) and negatively selected (it does not respond to normal you). It can recognize foreign things in the context of self-MHC, but it does not respond to self alone. It is, mostly, safe.
The total cost of this education is staggering. Of every hundred T cells that enter the thymus, perhaps two graduate. Ninety-eight die during training. Your body produces these cells constantly, throughout childhood and into adulthood, and almost all of them die without ever doing any work. The expense is enormous. The reason your body pays it is that the alternative — letting untested T cells out into circulation — would be far worse.
The Word ****“****Mostly****”
If you are reading carefully, you may have noticed a hedge in the last paragraph. T cells that graduate, I said, are mostly safe. Negative selection eliminates the great majority of self-reactive cells.
Mostly. Great majority. Not all.
Negative selection is good. It is not perfect. Some T cells with weak self-reactivity slip through. Some self-proteins are not displayed strongly enough in the thymus to be tested against. Some T cells whose receptors should have been deleted somehow weren’t. By the time the system is finished, every adult human is walking around with a small number of T cells in their bloodstream that, in principle, could attack their own tissues.
This is not a bug that biology forgot to fix. This is, more or less, an unavoidable feature of any system built on randomly generated receptors. The same V(D)J machinery that lets your immune system recognize anything will, occasionally, produce a self-reactive cell that the thymus misses.
So your body has a backup plan. Several, in fact.
The Second Layer
Even after T cells graduate from the thymus, there are additional checkpoints in the rest of the body, designed to keep the few self-reactive cells that escaped from causing trouble.
The most important of these is a population of T cells we briefly mentioned in the last chapter — regulatory T cells, often abbreviated Tregs (rhymes with “egg”). Tregs are not the killer T cells or helper T cells we’ve been discussing. They are a third class, with a different job: they actively suppress immune responses.
A Treg, when it encounters another T cell that is starting to mount a response against something the Treg considers harmless, releases cytokines that calm the other T cell down. Sometimes the Treg directly kills the over-eager cell. Sometimes it just dampens the response. The effect, throughout your body, is a constant low hum of “this is fine, this is fine, this is fine,” administered by a workforce of Tregs whose entire job is to prevent the immune system from getting too excited.
Tregs are especially abundant in places where the immune system encounters lots of harmless material that it should leave alone — in the gut, where they help maintain the peace with the microbiome we discussed in Chapter 5; in the skin; in the airways; and around developing fetuses, where they prevent the mother’s immune system from attacking the genetically half-foreign baby. (Pregnancy, immunologically, is one of the strangest tricks the human body pulls off, and Tregs are central to how it works. We’ll come back to this briefly later.)