Self & Other
7. The Schools of Tolerance
In the early 1960s, a young Australian-born immunologist named Jacques Miller was working in a London laboratory and doing something that, on the face of it, seemed almost embarrassing.
He was removing the thymus from baby mice.
The thymus, at the time, was considered something of a biological joke. It is a small, pinkish, two-lobed organ that sits behind the breastbone, just above the heart. It is largest in newborns and shrinks throughout life; by the time you are seventy, your thymus is mostly fat. For a long time, anatomists assumed it was a leftover — some evolutionary detail that hadn’t yet been pruned. There were textbooks that listed the thymus among the “vestigial organs,” in the same paragraph as the appendix.
When Miller proposed studying it, his supervisors were politely skeptical. The thymus had been opened, weighed, dissected, and stained for a century. People had looked. There was nothing there.
Miller went ahead anyway. He took baby mice, surgically removed their thymus glands within hours of birth, and then watched what happened as the mice grew up.
What happened was that the mice fell apart.
Without their thymus glands, the mice failed to grow normally. They became vulnerable to infections that other mice shrugged off. Their lymph nodes were nearly empty of cells. They could not reject foreign tissue — in fact, they accepted skin grafts from completely unrelated mice, the kind of grafts that would have been rejected within days by a normal animal. They were, immunologically, profoundly broken.
The thymus, it turned out, was not vestigial at all. It was, in some way, the source of an entire class of immune cells. Without a thymus, an animal grew up missing something fundamental.
Miller had discovered — though it took years to be fully understood — that the thymus is where T cells go to be made. Or, more precisely, where they go to be educated. T cells originate in the bone marrow, like all blood cells, but they leave the bone marrow young and naive, with their randomly generated V(D)J receptors not yet checked against the world. They travel through the bloodstream to the thymus, and they enter it. Most of them never come out.
The thymus is a school. It is one of the strangest schools in biology, partly because the curriculum is brutal, and partly because the goal of the curriculum is, in a sense, the opposite of what schools usually try to teach. Most schools try to make their students respond to things. The thymus is trying to make T cells learn what to ignore.
The Problem
To see why the school is necessary, recall the situation we left at the end of Chapter 6.
Every T cell carries a randomly generated receptor, courtesy of the V(D)J shuffling we met in Chapter 3. The shuffling is, deliberately, blind. It does not know what threats your body will encounter; it just spins out an enormous variety of receptors, on the bet that some of them will fit some of those threats. The strategy works beautifully. It is the reason your immune system can recognize, in principle, almost any molecule that has ever existed.
But the same blindness has a problem built into it. If the receptors are generated randomly, then some of them — by sheer chance — will recognize fragments of you. Not viruses, not bacteria, not pollen. You. Your own proteins, displayed on your own MHC molecules, on your own cells.
A T cell with that kind of receptor, if released into your body, would be a disaster. It would treat your healthy cells as if they were infected. It would call in the entire adaptive immune response — antibodies, killer cells, cytokines — against your own tissues. It would do, in miniature, exactly what happens in autoimmune disease.
The number of T cells with self-reactive receptors is not small. By some estimates, perhaps a third of all newly made T cells, drawn at random from the V(D)J lottery, would react against something in their own body if they were ever released. Maybe more. The system that produces antibody diversity, the same system that makes the immune system so flexible, generates self-attacking cells as a routine byproduct.
Your body has to find these cells before they can do damage. It has to find them quickly, when they are still young and few. It has to find them reliably, every time, your entire life. And it has to do this without a master list of “things that count as you,” because no such list exists. Your body has to figure out what counts as you on its own, locally, by inspection.
The thymus is how it does it.
Inside the School
A young T cell entering the thymus is in a strange situation. It has a randomly generated receptor and no idea what that receptor recognizes. It is about to be tested in two ways.
The first test is positive.
In the outer layer of the thymus, called the cortex, the young T cell encounters a population of specialized thymic cells whose job is to display a wide range of self-MHC molecules — the same molecules the T cell will eventually have to read in the rest of the body. The young T cell sniffs around, in molecular terms, trying to recognize what it sees.
If it can’t recognize the self-MHC molecules at all — if its randomly generated receptor is so far off that it can’t even bind weakly to the body’s flashcards — it fails the test. It will be useless, because every T cell needs to be able to read the cards in the first place. A T cell that can’t see the cards has no way of finding anything. It is told, in chemical language, to die. It dies. The macrophages clean up.