A new way in which T cells learn to distinguish friend from foe

The human immune system is a nearly perfect defense mechanism. It protects the body from bacteria, viruses and other pathogens. It recognizes incipient tumors and eliminates them. It cleans cellular debris at the site of injury or infection.

In order to fulfill its myriad functions, the immune system must first and foremost distinguish between self and non-self—a remarkable selective ability that allows it to recognize and deactivate harmful agents while sparing the body’s own tissues.

When the immune system fails to make this distinction, it can mistakenly launch an attack on the body and cause autoimmune diseases.

Researchers have known the general principle behind this selective ability for some time, but how exactly immune cells learn to distinguish friend from foe is even less well understood.

Now, a new study by researchers at Harvard Medical School identifies a new mechanism that explains how the body’s strongest immune troops — T cells — learn to distinguish themselves from non-self.

The work, conducted primarily in mice, was published online on June 16 cell and is scheduled to appear in the July 7 print edition.

Research shows that the thymus gland — the organ where T cells are born and made — trains nascent immune cells by exposing them to proteins made by thymus cells that mimic various tissues throughout the body. In particular, the research shows that by adopting different identities, these specialized thymus cells are given a preview of the maturing T-cell self-proteins they would encounter once they exit their native thymus.

“Imagine recreating your body inside the thymus gland,” said the study’s lead author Diane Mathis, a professor of immunology at Harvard Medical School. “It was a revelation for me to be able to see muscle-like cells in the thymus gland or to see several very different types of intestinal cells with my own eyes. »

According to Mathis, the results shed light on how the adaptive immune system acquires its ability to distinguish friend from foe. Problems in this critical detection system can have serious consequences.

“Our immune system is super strong. It can kill every cell in our body, it can control every pathogen we encounter, but with that power comes great responsibility,” said study lead author Daniel Michelson, a MD/PhD student at Harvard Medical School. and researchers in the Mathis/Benoist laboratory. “If this power is not controlled, it can be deadly. In some autoimmune diseases it is is deadly. »

The school of T cells

T cells, so named because they mature and learn to do their job in the thymus before being released into the body, are the elite forces of the immune system, endowed with multiple functions. They recognize and eliminate pathogens and cancer cells; they form the long-term memory of viruses and bacteria encountered in the past; they regulate inflammation and dampen overactive immunity.

But how does a newborn T cell that has never left the thymus know which proteins are unique to the body and which herald enemy presence?

“T cells are made in the thymus, but the thymus isn’t an intestine, it’s not a pancreas,” Michelson said. “There’s no reason these T cells should be able to recognize these organs before they leave the thymus. »

The researchers knew that this early formation took place in the thymus gland, but the exact teaching tools the gland uses eluded them.

A molecular explanation for a centuries-old sighting

Until the mid-20th century, the thymus attracted little scientific interest because it was thought to be vestigial, Michelson said. But by the mid-1700s—long before scientists knew what the thymus did or an adaptive immune system existed—biologists had already noticed cells in the thymus that looked out of place. Over the decades, through their microscopes, they saw cells that appeared to be from muscle, gut, and skin. But the thymus was none of that. The comments made no sense.

The newly published research takes a very old discovery and puts it in an entirely new molecular context, Michelson said.

The study showed that these teacher cells, called mimetic cells for their ability to mimic different tissues, function by co-opting different transcription factors – proteins that drive the expression of genes unique to certain tissues. When they do so, the mimetic cells effectively take on the identity of tissues such as skin, lungs, liver, or intestines. They then present themselves to immature T cells to teach them self-tolerance, the team’s experiments showed.

The work shows that nascent T cells that mistakenly react against self-proteins are given an order to self-destruct or are redirected to other types of T cells that don’t kill but instead stop other immune cells from attacking.

“The thymus says this cell is self-reactive, we don’t want it in our repertoire, let’s get rid of it,” Michelson said.

rebound

Until now, it has been assumed that the elimination of autoreactive T cells is largely regulated by a single protein called AIRE. The Mathis/Benoist laboratory has played an essential role in elucidating the function of AIRE. Defects in this protein can lead to severe immune syndrome, which is characterized by the development of various types of autoimmune diseases.

Mathis and Michelson continued their current research by attempting to map the molecular pathways involved in AIRE function. Instead, they found many cells in the thymus that did not express the AIRE protein but could still assume the identities of different tissue types. The researchers realized that AIRE was only part of the story.

The researchers say the newly identified mimetic cells likely play a role in various autoimmune diseases related to the types of tissues they mimic, a hypothesis they plan to pursue.

“We think this is an exciting discovery that could open up a whole new perspective on how certain types of autoimmune diseases arise and, more generally, the origins of autoimmunity,” Mathis said.

The researchers said their next steps are to gain an even deeper understanding of the molecular mechanisms underlying T cell formation, examine the association between individual mimetic cell types and lymphocyte function and dysfunction, and determine how the mechanism in humans. Thymus.

Study co-authors included Koji Hase from Keio University, Tsuneyasu Kaisho from Wakayama Medical University and Christophe Benoist from HMS.

The work was supported by National Institutes of Health grants R01AIo88204, Ro1DKo60027, and T32GM007753.

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