Thymus gland educates nascent immune cells by exposing them to proteins made by thymus cells that mimic various tissues throughout the body


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 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—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 at Harvard Medical School. “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/Ph.D. student at Harvard Medical School 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.

Optimal immunological response to a large array of unknown antigens requires the presence of a diverse T-cell receptors (TCRs) repertoire, which represents the primary determinant for the likelihood of recognizing specific antigens (1). The thymus is the primary lymphoid organ with the exclusive role for generating and maintaining in the periphery a broadly diverse pool of T cells able to recognize tumor and pathogenic antigens.

Once considered to take only a marginal part in maintaining a healthy immune system in adult life, the adult thymus plays a crucial role in sustaining the peripheral TCR repertoire diversity under physiological and clinical conditions. Thymic function and T-cell output are dynamic processes that can be severely compromised by acute immunological insults (resulting from infections, stress or antineoplastic therapies) and by chronic dysfunctions (such as the ones correlated to age-associated involution and recurrent infections).

Suboptimal thymic function and skewed TCR repertoire can have profound immunological and clinical consequences for patients’ response to different forms of immunotherapy (Figure 1).

Figure 1
Overview of the factors affecting thymic function and their potential role in regulating patients’ response to checkpoint blockade immunotherapy. Thymus is particularly sensitive to negative insults that can come from infections, stress, cytoreductive therapies and the physiological process of aging (yellow boxes). The reduction in thymic functionality and in the TCR diversity impaired immune surveillance and may provide a supportive environment for tumors to elude T-cell-mediated response. Instead, a broader TCR repertoire in patients receiving CBI would increase the chance of tumor antigen recognition and favorable long-term clinical outcome. The use of regenerative factors aimed to boost thymic function could improve TCR repertoire diversity and have the potential to significantly extend the clinical efficacy of CBI. TCR, T cell repertoire; CBI, checkpoint blockade immunotherapy; SSA, sex steroids ablation.

Thymic Function and the Generation of a Diverse TCR Repertoire

During the process of T-cell development, thymocytes undergo a series of well-characterized and sequential developmental steps that ultimately lead to the formation of CD4 or CD8 single-positive T cells. These developmental steps are orchestrated by the crosstalk between bone marrow (BM)-derived T-cell progenitors and the supportive thymic stromal microenvironment, which primarily consists of thymic epithelial cells (TECs), endothelial cells (ECs), mesenchymal cells, dendritic cells and macrophages (2). A crucial step in T-cell development process is the generation of TCR molecules able to recognize antigenic peptides presented on heterologous cells. The recognition of a specific antigen is granted by three complementarity-determining regions (CDRs) of the TCR. The CDR3 regions are generated by somatic rearrangement between noncontiguous variable (V) and joining (J) gene segments for α and γ loci and between V, diversity (D), and J segments for the β and δ loci. The existence of multiple V, D and J gene segments in germline DNA allows the generation of a large variety of distinct CDR3 sequences that can be encoded (3). TCR rearrangement occurs in the thymic cortical and medullary regions where, respectively, the positive and negative selection of developing thymocytes occurs (4). Once the formation of a functional TCR is completed, T cells leave the thymus and enter the circulation where they impact the peripheral TCR diversity, specifically, of the naïve T-cell compartment.

The integrity of thymic function is essential for the generation of T cells with a diverse TCR. However, the thymus is particularly susceptible to negative insults that can come from infections, stress, acute and chronic Graft-versus-Host disease, cytoreductive therapies such as chemo and radiotherapy (5). These effects lead to a qualitative and quantitative decline in T-cell output with consequent restricted TCR repertoire diversity and impaired immune responses. At a specific time of an individual’s life, the peripheral diversity of TCR repertoire reflects and is shaped by multiple intrinsic and extrinsic factors, including the residual thymic functionality, previous response to pathogens, previous diseases and therapies, and many others.

In addition, the physiological process of aging has important effects on thymic function and TCR diversity. While the adult thymus can still generate new T cells up to the seventh decade of life, this process is severely compromised (6–8). It is well recognized that the size of peripheral naïve T-cell pool and the functionality of the immune system progressively decline with age (9). Particularly, aging impairs the normal process of T-cell development at multiple levels, including reduced numbers of lymphoid progenitors generated in the BM, decreased clonal deletion during negative selection (which increases the risk of releasing autoreactive T cells in the periphery), altered thymic microenvironment, reduced output of new T cells (6, 10). As a result, it has been estimated that only ~30–40% of elderly people are capable of mounting sufficient immune responses to the influenza vaccine (11). In addition, studies in pre-clinical models linked the skewed TCR repertoire occurring during aging to infection susceptibility (12). Although in healthy individuals thymic involution is not associated with any clinical consequences, the age-associated decline of thymic function significantly impairs the endogenous process of thymic repair following cytoreductive therapies further delaying the immune reconstitution in cancer patients (6).

Overall, reduction in thymic functionality and in the peripheral T-cell diversity are important contributors of the decline in immune surveillance observed in the elderly and this may eventually provide a supportive environment for infections and tumors to elude T-cell-mediated response. Even though there is a temporal correlation, the connection between decreased thymic function and increased incidence of cancers during age is still largely debated (13, 14).

reference link :

More information: Daniel A. Michelson et al, Thymic epithelial cells co-opt lineage-defining transcription factors to eliminate autoreactive T cells, Cell (2022). DOI: 10.1016/j.cell.2022.05.018


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