IRIC - Institute for Research in Immunology and Cancer

Published on November 29, 2017

Why does the thymus ages faster than other organs? Important advance in the prevention of aging of the thymus: summary of the article from the Perreault lab in Cell Reports.

The team of Dr. Claude Perreault, Principal Investigator and Director of the Immunobiology Research Unit at IRIC, co-published an article in the scientific journal Cell Reports concerning the aging of the thymus, an organ essential for the development of the immune system. The shed study is the result of a collaboration with Dr. Louis Gaboury, also Principal Investigator at IRIC, and for his part, Director of the Histology and Molecular Pathology Research Unit.

Claude Perreault and his team study the “T lymphocytes”, the cells that control the functioning of the immune system, in order to better understand it, improve it and prevent its aging.

One of their main research interests is the thymus. They seek to determine why it is the only organ capable of supporting the development of T cells, how these cells learn to distinguish the self from the non-self in the thymus and how they can recognize cancer cells, with the aim of ultimately increasing their antitumor activity.

Colonies of thymic epithelial cell progenitors isolated from wild (left) or IP deficient (right) mice. Green: mTECs; Red: cTECs; Blue: cell nuclei.

Focus on the study

In multicellular organisms, the self/non-self recognition is a key concept governing immune defenses. For T cells, this skill is shaped in the thymus by medullary thymic epithelial cells (mTECs). However, although there is no substitute organ for the thymus in the animal kingdom, premature aging of the thymus is the most common immunopathology in humans. In particular, thymic involution increases susceptibility to infections and autoimmune diseases, and also alters the responses to immunization and immunosurveillance of cancer cells.

Since this phenomenon is conserved in vertebrates, the team used the mouse as a model system to better understand the etiological factors of thymic involution. Their research has highlighted a new mechanism for thymic involution with great explanatory power.

Although immune self-tolerance is a vital process, their work supports a new paradigm whereby the price to pay for inducing self-tolerance is an increase in proteotoxic stress and accelerated thymic degeneration. Specifically, they discovered that in the absence of the immunoproteasome (IP), a molecular machinery that rids the cell of overabundant or defective proteins, this susceptibility to stress dramatically increases in mTECs, leading to rapid depletion of the progenitors of these cells. In addition, the IP deficient mice display precipitated thymic involution characterized by a selective loss of mTECs and a multi-organ autoimmune syndrome.

In other words, if the thymus didn’t have to work so hard to massively get rid of a high number of proteins, it would stay younger, for a longer period and would equip our immune system against pathological assailants, notably, cancers.

The results thus demonstrate that the induction of self-tolerance by mTECs represents a major burden for the maintenance of protein homeostasis and that this proteotoxic stress is attenuated by the constitutive expression of the IP (acting as a major regulator) in mTECs. Finally, the research performed at IRIC proposes a potential biological target to design new strategies to prevent aging of the thymus and thus strengthening the immune system.

To read the full article, visit: https://doi.org/10.1016/j.celrep.2017.10.121

Study cited

St-Pierre, C., Morgand, E., Benhammadi, M., Rouette, A., Hardy, M.-P., Gaboury, L., Perreault, C. (2017) Immunoproteasomes control the homeostasis of medullary thymic epithelial cells by alleviating proteotoxic stress. Cell Reports 21, 1-13.

Thank you to Charles St-Pierre, first author of the study, for his contribution to this summary.

The absence of immunoproteasomes (IP) increases susceptibility to proteotoxic stress and accelerates thymic involution. In mice, the absence of IP results in a selective loss of medullary thymic epithelial cells (mTECs), which causes autoimmune manifestations in several organs.