Sweetbread, à la Immune System

Here’s a recipe straight from our body’s cookbook: how to train immune cells to efficiently eliminate invading viruses and bacteria, while leaving our own cells unharmed. The star ingredient? The thymus. Just like in sweetbread!

Artwork by Alice Bongers

If I asked you to name a few organs tucked away in your chest, you’d probably say, “the heart.” That’s an easy one, we can sometimes hear it pounding, and also the lungs. But what about the thymus? No? Ever heard of sweetbread, then? You might’ve eaten it without knowing it’s actually made from a calf’s thymus... A handy little tidbit for your next dinner party!

Yes, just like calves—and pretty much all mammals—we humans have an organ called the thymus, located in our chest right above the heart. But what does it do? And why do we eat calf sweetbread but not beef sweetbread?

The thymus is basically elementary school for our immune system’s cells. It’s where immune cells go to learn the ABCs of their future job. This organ, like the bone marrow, is what we call a “primary lymphoid organ.” Most of our white blood cells are made in the bone marrow from stem cells—the “mother” cells of all blood cells. Many of these then need to pass through the thymus for a solid education before moving out to the front lines: the lymph nodes and spleen. These are our secondary lymphoid organs, where immune cells are fully geared up to defend us from external threats like bacteria and viruses.

Among our white blood cells, we have the T cells (I’ll let you guess what the “T” stands for…). These are crucial soldiers in our immune defense; they are trained to deal with specific invaders, and they have something remarkable: memory. If a T cell meets a pathogen once, it remembers it, and this allows our immune system to respond faster and better the next time around. This is basically what vaccines aim to mimic: they let T cells “meet” a harmless version of a virus or bacteria, so when the real thing shows up, the immune system reacts quickly and efficiently to protect us.

But to be effective, T cells have to go through a pretty brutal selection process in the thymus. The goal? To create T cells that, hypothetically, can recognize any foreign intruder that could harm us. Easy, say the geneticists: just give the cells an arm they can endlessly mutate to grab any stranger. This arm is called the TCR (T Cell Receptor), and part  of it can be shuffled almost infinitely during the early development of T cells in the thymus. We’re talking about genetic rearrangement that can theoretically generate up to 10¹⁵ different TCRs (that’s a million billion options—about 100,000 times more than there are humans on Earth). In theory. In practice, not all these combinations work out (think Lego bricks: sure, you can try a million designs, but some just won’t hold together). 

But wait, there’s more! This TCR doesn’t just need to hold together, it also has to recognize what’s being shown to it. T cells don’t go out and find pathogens on their own. They wait in the secondary organs for something to be presented to them. That job goes to sentinel cells also called antigen-presenting cells, or APCs (immunologists love acronyms, just so you know). These cells patrol the body and, when they spot something suspicious, they bring a sample to the T cells.

And it’s not the whole pathogen they bring, but a little snippet of it—called an antigen. APCs also have their own presenting “arm” called MHC (Major Histocompatibility Complex). So the TCR needs to recognize this MHC-antigen duo. That recognition is crucial because it’s what allows the T cell to launch a targeted strike on the intruder.

In the thymus, T cells learn to recognize this MHC-antigen pair. This is known as positive selection. Thymic cells present antigens to the developing T cells: if a T cell’s TCR can recognize the combo, it moves onto the next round. If not? Eliminated.

Now, you might already be wondering: if TCRs are created randomly, couldn’t some of them accidentally recognize parts of our own body? Wouldn’t that be dangerous? You bet! That’s exactly what happens in autoimmune diseases, when the immune system mistakes our own cells for enemies.

To prevent this, there’s a second round of selection called negative selection. Here, thymic cells present self-antigens: pieces of our own tissues. If a T cell reacts to these, it’s marked “self-reactive” and gets eliminated. This step teaches the immune system tolerance: to ignore what belongs to us. This is also known as central tolerance, because in thymus-speak, the thymus is the “center”, and the rest of the body is the “periphery” (kind of like how Parisians see the world: Paris and then… everything else). So, if all goes according to plan, after these two rounds of selection, the thymus releases T cells that recognize foreign threats and ignore our own tissues. In short: defenders, not self-destructors.

But life is rarely perfect. Some self-reactive T cells do manage to sneak out into the “periphery”—oops, I mean, the rest of the body. What’s the risk? You guessed it: autoimmune diseases. That’s when the immune system turns on us, mistakenly attacking organs it thinks are enemies (like the pancreas in type 1 diabetes). Without treatment, this can be deadly.

The good news: our body has a backup plan! Several mechanisms exist to control rogue T cells outside the thymus : this is called peripheral tolerance. One key player actually comes from the thymus itself. During the second selection round, not all self-reactive T cells are destroyed. Some go through a sort of career change and become regulatory T cells, or Tregs. Tregs act like immune system moderators. They keep other T cells in check and help end the immune response once the danger is gone. They’re crucial for preventing autoimmunity: without Tregs, people develop severe diseases early in life and have a very limited life expectancy.

Despite all this, some people still develop autoimmune conditions like type 1 diabetes, multiple sclerosis, lupus, ankylosing spondylitis, and more. In these cases, something goes wrong with one or more tolerance mechanisms. While we don’t always know what triggers these failures, we do know that several factors are involved (genetics, environment, stress, diet...). The scientific community is working hard to better understand these conditions, and new treatments are emerging that vastly improve quality of life.

And here’s a final fun fact: the thymus shrinks as you age. That’s why we eat calf sweetbread and not cow sweetbread—because adult mammals barely have a thymus anymore. Why? Great question—we’re still not totally sure. But we do know the thymus is most active in early childhood, helping populate the body with T cells and Tregs. That’s one of many reasons why a healthy, low-stress environment during a child’s first years is so important: good food, balanced living, and lots of love!

Acknowledgments:

Thank you to my colleagues and friends Ana Choï, Sophie Dulauroy, Lucette Polomack, and my supervisor Gérard Eberl for reviewing this piece.

This article was copy edited by Marie Juzans.

Meet the author: Cécile Apert