Study identifies a new mechanism that explains how immune cells learn to distinguish friend from foe

The human immune system is an almost perfect defense mechanism. It protects the body against disease-causing bacteria, viruses and other pathogens. It detects budding tumors and eradicates them. It clears up cell debris at the site of injury or infection.

Above all, to perform its myriad functions, the immune system must distinguish between self and non-self – a remarkable selective ability that allows it to detect and disable harmful substances while sparing the body’s own tissues.

If the immune system doesn’t make this distinction, it can mistakenly attack the body, causing autoimmune diseases.

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

Now, a new study led by Harvard Medical School researchers identifies a novel mechanism that explains how the body’s most powerful immune forces;T cells-; learn to distinguish self and non-self.

The work, mainly performed on mice, was published online June 16 in Cell and is scheduled to appear in the July 7 print issue. The research shows that the thymus gland, the organ where T cells are born and trained, nurture budding immune cells by exposing them to proteins made by thymus cells that mimic various tissues. the body. In particular, the research shows that by assuming different identities, these specialized thymus cells are a foretaste of the maturing T cells self-proteins they would encounter once they leave their native thymus gland.

See it as if your body is being recreated in the thymus. For me it was a revelation to be able to see muscle-like cells in the thymus or some very different types of intestinal cells with my own eyes.”

Diane Mathis, senior author of the study, professor of immunology at Harvard Medical School

The findings, Mathis said, shed light on how the adaptive immune system acquires its ability to distinguish friend from foe. Failures in this critical recognition system can have serious consequences.

“Our immune system is super powerful. It can kill every cell in our body, it can control every pathogen we come across, but with that power comes a lot of responsibility,” said lead researcher Daniel Michelson, an MD/PhD researcher. student at Harvard Medical School. and a researcher in the Mathis/Benoist lab. “If that power is not controlled, it can be fatal. In some autoimmune diseases, it is” is deadly.”

School for 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 charged with multiple functions. They recognize and eliminate pathogens and cancer cells; they form a long-term memory of viruses and bacteria encountered in the past; they regulate inflammation and suppress hyperactive immunity.

But how does a newborn T cell that has never left the thymus know which proteins are the body’s and which announce the presence of the enemy?

“T cells are trained in the thymus, but the thymus is not a gut, it is not a pancreas,” Michelson said. “There’s no reason why these T cells should be able to recognize these organs before they leave the thymus.”

Researchers knew that this early training does indeed take place in the thymus, but the precise learning tools the gland uses have eluded them.

A molecular explanation for an age-old observation

Until the mid-20th century, the thymus aroused little scientific interest because it was considered vestigial, Michelson said. But as early as the mid-1800s — long before scientists knew what the thymus does or whether an adaptive immune system existed — biologists had noticed cells in the thymus that seemed out of place. Peering through the decades in their microscopes, they saw cells that looked like they came from muscle, gut and skin. Yet the thymus was none of the above. The observations made no sense.

The newly published research references a very old finding 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, work by combining different transcription factors, proteins that direct the expression of genes unique to specific tissues. When they do this, the mimetic cells effectively take on the identity of tissues such as skin, lung, liver or gut. They then present themselves to immature T cells to teach them self-tolerance, the team’s experiments showed.

The work shows that T cells in training that mistakenly react against self proteins are either commanded to self-destruct or are reused in other types of T cells that don’t kill, but instead stop other immune cells from attacking. fall.

“The thymus says: This cell is autoreactive, we don’t want it in our repertoire, let’s get rid of it,” Michelson said.

plot twist

Until now, the elimination of self-reactive T cells was thought to be largely regulated by a single protein called AIRE. The Mathis/Benoist lab was instrumental in elucidating the function of AIRE. Defects in this protein can lead to a severe immune syndrome characterized by the development of multiple types of autoimmune diseases.

Mathis and Michelson focused on mapping the molecular pathways involved in AIRE function in their current study. Instead, they found many cells in the thymus that did not express the AIRE protein, yet were able to take over the identity of different tissue types. AIRE, the researchers realized, was only part of the story.

The researchers say the newly identified mimetic cells likely play a role in several autoimmune diseases linked to the tissue types they mimic, a hypothesis they plan to pursue.

“We think it’s an exciting discovery that could open up a whole new vision of how certain types of autoimmune diseases arise and, more broadly, 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 education, to study the association between individual mimetic cell types and T cell function and dysfunction, and to determine how the mechanism plays out in humans. thymus.


Reference magazine:

Michelson, D.A., et al. (2022) Thymic epithelial cells co-opt lineage-determining transcription factors to eliminate autoreactive T cells. Cell

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