From The Harvard Medical School: “Boot Camp for the Immune System”


From The Harvard Medical School


Harvard University

June 27, 2022

News & Research

How immune cells learn to discern friend from foe

The thymus gland, shown here, is the birthplace and training ground of T cells. New research shows thymus cells assume various identities to teach nascent T cells how to distinguish friend from foe. Image: Daniel Michelson, Mathis/Benoist lab, HMS.

The human immune system is a nearly perfect defense mechanism. It protects the body from disease-causing bacteria, viruses, and other pathogens. It detects nascent tumors and eradicates them. It cleans up cellular debris at the site of injury or infection.

To perform its myriad functions, the immune system must, above all, differentiate between self and non-self—a remarkable selective ability that allows it to detect and disable harmful agents while sparing the body’s own tissues.

If the immune system fails to make this distinction, it can mistakenly launch an assault against the body, causing autoimmune disorders.

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

Now, a new study led by researchers at Harvard Medical School identifies a new mechanism that explains how the body’s most powerful immune troops—T cells—learn to tell self and non-self apart.

The work, conducted mainly in mice, was published online June 16 in Cell.

The research shows that the thymus gland—the organ where T cells are born and trained—educates nascent immune cells by exposing them to proteins made by thymus cells that mimic various tissues throughout the body. Specifically, the research demonstrates that by assuming different identities, these specialized thymus cells preview for the maturing T cells self-proteins they would encounter once they leave their native thymus gland.

“Think of it as having your body recreated in the thymus,” said study senior author Diane Mathis, professor of immunology in the Blavatnik Institute at HMS. “For me, it was a revelation to be able to see with my own eyes muscle-like cells in the thymus or several very different types of intestinal cells.”

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

“Our immune system is super powerful. It can kill any cell in our body, it can control any pathogen we encounter, but with that power comes great responsibility,” said study first author Daniel Michelson, an MD/PhD student at HMS and a researcher in the Mathis/Benoist lab. “If that power is left unchecked, it can be lethal. In some autoimmune diseases, it is lethal.”

School for T cells

T cells, so named because they mature and learn to do their job in the thymus before they are released into the body, are the immune system’s elite forces charged with multiple functions. They recognize and eliminate pathogens and cancer cells; they form long-term memory of viruses and bacteria encountered in the past; they regulate inflammation and tamp down hyperactive immunity.

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

“T cells get educated in the thymus, but the thymus is not a gut, it’s 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 take place in the thymus, but the precise teaching tools the gland uses have eluded them.

A molecular explanation for a centuries-old observation

Until the mid-1900s, the thymus provoked little scientific interest because it was deemed vestigial, Michelson said. But as far back as the mid-1800s—well before scientists knew what the thymus does or that an adaptive immune system existed—biologists had already noticed cells in the thymus that looked out of place. Peering into their microscopes throughout the decades, they saw cells that looked like they came from muscle, intestine, and skin. Yet, the thymus was none of the above. The observations made no sense.

The newly published research hearkens back to a very old finding and puts it into a whole new molecular context, Michelson said.

The study showed that these teacher cells, dubbed mimetic cells for their ability to mimic different tissues, work by co-opting various transcription factors—proteins that drive the expression of genes unique to specific tissues. When they do so, the mimetic cells effectively adopt the identities of tissues such as skin, lung, liver, or intestine. 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 either receive a command to self-destruct or get repurposed into other types of T cells that don’t kill but instead restrain other immune cells from attacking.

“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 regulated largely by a single protein called AIRE. The Mathis/Benoist lab was critical in elucidating the function of AIRE. Defects in this protein can lead to a serious immune syndrome characterized by the development of multiple types of autoimmune disorders.

Mathis and Michelson went into their current research seeking 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 were still capable of adopting the identities of different tissue types. AIRE, the researchers realized, was only part of the story.

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

“We think it’s an exciting discovery that may open up a whole new vision of how certain types of autoimmune diseases arise and, more broadly, of the origins of autoimmunity,” Mathis said.

The researchers said their next steps are to acquire an even deeper understanding of the molecular mechanisms that underlie 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 the human thymus.

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

The work was funded by National Institutes of Health grants R01AI088204, R01DK060027, and T32GM007753.

See the full article here .


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Harvard University is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s bestknown landmark.

Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

The Massachusetts colonial legislature, the General Court, authorized Harvard University (US)’s founding. In its early years, Harvard College primarily trained Congregational and Unitarian clergy, although it has never been formally affiliated with any denomination. Its curriculum and student body were gradually secularized during the 18th century, and by the 19th century, Harvard University had emerged as the central cultural establishment among the Boston elite. Following the American Civil War, President Charles William Eliot’s long tenure (1869–1909) transformed the college and affiliated professional schools into a modern research university; Harvard became a founding member of the Association of American Universities in 1900. James B. Conant led the university through the Great Depression and World War II; he liberalized admissions after the war.

The university is composed of ten academic faculties plus the Radcliffe Institute for Advanced Study. Arts and Sciences offers study in a wide range of academic disciplines for undergraduates and for graduates, while the other faculties offer only graduate degrees, mostly professional. Harvard has three main campuses: the 209-acre (85 ha) Cambridge campus centered on Harvard Yard; an adjoining campus immediately across the Charles River in the Allston neighborhood of Boston; and the medical campus in Boston’s Longwood Medical Area. Harvard University’s endowment is valued at $41.9 billion, making it the largest of any academic institution. Endowment income helps enable the undergraduate college to admit students regardless of financial need and provide generous financial aid with no loans The Harvard Library is the world’s largest academic library system, comprising 79 individual libraries holding about 20.4 million items.

Harvard University (US) has more alumni, faculty, and researchers who have won Nobel Prizes (161) and Fields Medals (18) than any other university in the world and more alumni who have been members of the U.S. Congress, MacArthur Fellows, Rhodes Scholars (375), and Marshall Scholars (255) than any other university in the United States. Its alumni also include eight U.S. presidents and 188 living billionaires, the most of any university. Fourteen Turing Award laureates have been Harvard affiliates. Students and alumni have also won 10 Academy Awards, 48 Pulitzer Prizes, and 108 Olympic medals (46 gold), and they have founded many notable companies.


Harvard University was established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. In 1638, it acquired British North America’s first known printing press. In 1639, it was named Harvard College after deceased clergyman John Harvard, an alumnus of the University of Cambridge(UK) who had left the school £779 and his library of some 400 volumes. The charter creating the Harvard Corporation was granted in 1650.

A 1643 publication gave the school’s purpose as “to advance learning and perpetuate it to posterity, dreading to leave an illiterate ministry to the churches when our present ministers shall lie in the dust.” It trained many Puritan ministers in its early years and offered a classic curriculum based on the English university model—many leaders in the colony had attended the University of Cambridge—but conformed to the tenets of Puritanism. Harvard University has never affiliated with any particular denomination, though many of its earliest graduates went on to become clergymen in Congregational and Unitarian churches.

Increase Mather served as president from 1681 to 1701. In 1708, John Leverett became the first president who was not also a clergyman, marking a turning of the college away from Puritanism and toward intellectual independence.

19th century

In the 19th century, Enlightenment ideas of reason and free will were widespread among Congregational ministers, putting those ministers and their congregations in tension with more traditionalist, Calvinist parties. When Hollis Professor of Divinity David Tappan died in 1803 and President Joseph Willard died a year later, a struggle broke out over their replacements. Henry Ware was elected to the Hollis chair in 1805, and the liberal Samuel Webber was appointed to the presidency two years later, signaling the shift from the dominance of traditional ideas at Harvard to the dominance of liberal, Arminian ideas.

Charles William Eliot, president 1869–1909, eliminated the favored position of Christianity from the curriculum while opening it to student self-direction. Though Eliot was the crucial figure in the secularization of American higher education, he was motivated not by a desire to secularize education but by Transcendentalist Unitarian convictions influenced by William Ellery Channing and Ralph Waldo Emerson.

20th century

In the 20th century, Harvard University’s reputation grew as a burgeoning endowment and prominent professors expanded the university’s scope. Rapid enrollment growth continued as new graduate schools were begun and the undergraduate college expanded. Radcliffe College, established in 1879 as the female counterpart of Harvard College, became one of the most prominent schools for women in the United States. Harvard University (US) became a founding member of the Association of American Universities in 1900.

The student body in the early decades of the century was predominantly “old-stock, high-status Protestants, especially Episcopalians, Congregationalists, and Presbyterians.” A 1923 proposal by President A. Lawrence Lowell that Jews be limited to 15% of undergraduates was rejected, but Lowell did ban blacks from freshman dormitories.

President James B. Conant reinvigorated creative scholarship to guarantee Harvard University’s preeminence among research institutions. He saw higher education as a vehicle of opportunity for the talented rather than an entitlement for the wealthy, so Conant devised programs to identify, recruit, and support talented youth. In 1943, he asked the faculty to make a definitive statement about what general education ought to be, at the secondary as well as at the college level. The resulting Report, published in 1945, was one of the most influential manifestos in 20th century American education.

Between 1945 and 1960, admissions were opened up to bring in a more diverse group of students. No longer drawing mostly from select New England prep schools, the undergraduate college became accessible to striving middle class students from public schools; many more Jews and Catholics were admitted, but few blacks, Hispanics, or Asians. Throughout the rest of the 20th century, Harvard became more diverse.

Harvard University’s graduate schools began admitting women in small numbers in the late 19th century. During World War II, students at Radcliffe College (which since 1879 had been paying Harvard University professors to repeat their lectures for women) began attending Harvard University classes alongside men. Women were first admitted to the medical school in 1945. Since 1971, Harvard University has controlled essentially all aspects of undergraduate admission, instruction, and housing for Radcliffe women. In 1999, Radcliffe was formally merged into Harvard University.

21st century

Drew Gilpin Faust, previously the dean of the Radcliffe Institute for Advanced Study, became Harvard University’s first woman president on July 1, 2007. She was succeeded by Lawrence Bacow on July 1, 2018.