Medullary thymic epithelial cells, or mTECs, are specialized cells in the inner region of the thymus, a gland positioned behind the sternum. These cells function as the immune system’s educators, preventing autoimmunity by teaching developing immune cells, called T cells, to distinguish between the body’s own components and foreign invaders. This process ensures that only T cells safe for self-tissues are permitted to circulate throughout the body.
The Thymus as a T Cell Training Ground
The thymus is the principal organ for T cell maturation. T cell progenitors originate in the bone marrow and travel to the thymus, which is divided into an outer cortex and an inner medulla. A developing T cell, or thymocyte, begins its journey in the cortex and progresses inward to the medulla.
In the cortex, thymocytes undergo positive selection, where cortical thymic epithelial cells (cTECs) test their T cell receptors (TCRs). These receptors must bind to major histocompatibility complex (MHC) proteins, which present antigens on the cell surface. Thymocytes with receptors that cannot recognize MHC molecules are eliminated.
Surviving thymocytes migrate to the medulla, the final checkpoint and the domain of mTECs. The medulla provides the microenvironment where T cells are examined to prevent autoimmunity. Here, mTECs remove self-reactive cells before they are released into the body.
Mechanism of Central Tolerance Induction
The goal within the thymic medulla is to establish central tolerance, the immune system’s ability to not attack its own tissues. This is achieved by eliminating T cells that react too strongly to the body’s own proteins. mTECs are equipped for this through promiscuous gene expression, allowing them to produce thousands of tissue-restricted antigens (TRAs) normally found only in specific organs, such as insulin from the pancreas.
This capability is controlled by a protein called the Autoimmune Regulator (AIRE). AIRE functions as a transcription factor, enabling mTECs to express a vast library of the body’s self-antigens. By creating this representation of the body’s tissues within the thymus, mTECs can simulate what a T cell might encounter in other parts of the body.
The presentation of these TRAs by mTECs initiates negative selection. As thymocytes survey the antigens displayed on mTEC surfaces, their fate is determined by binding strength. If a T cell’s receptor binds too strongly to a self-antigen, it is identified as a potential threat and instructed to undergo apoptosis, a form of programmed cell death.
In some cases, instead of being destroyed, T cells that recognize self-antigens can develop into regulatory T cells (Tregs). These Tregs are then released into the body, where they actively suppress any self-reactive T cells that may have escaped deletion. This dual approach provides a strong system for maintaining self-tolerance.
Consequences of mTEC Dysfunction
When the mTEC process falters, the immune system can fail to learn self-tolerance, leading to autoimmune diseases. The consequences are clearly illustrated by a rare genetic disorder called Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). This condition arises from mutations in the AIRE gene, which enables promiscuous gene expression in mTECs.
Without functional AIRE, mTECs cannot express the wide array of tissue-specific antigens for negative selection. As a result, T cells reactive to the body’s own proteins are not eliminated within the thymus. These autoreactive T cells are then released into the bloodstream, where they can attack the body’s organs.
The clinical manifestations of APECED reflect this breakdown in central tolerance. Patients often experience chronic yeast infections (candidiasis) and suffer from autoimmune attacks on multiple endocrine glands. The most commonly affected are the parathyroid glands, leading to hypoparathyroidism, and the adrenal glands, causing Addison’s disease.
Development and Maturation of mTECs
Medullary thymic epithelial cells originate from progenitor cells at the boundary between the cortex and medulla. Developing T cells play a part in this maturation by providing signals, such as RANKL and CD40L, to the progenitor cells. These interactions drive the developmental program that results in a functional thymic medulla.
Several transcription factors and signaling pathways shape the mTEC population. Beyond AIRE, pathways like the NF-κB signaling pathway are involved in the development and survival of these cells. For instance, the proteins NIK and IKKα are components of this pathway, and their absence can halt mTEC development, leading to a breakdown of central tolerance and autoimmunity in animal models.
The mTEC population is maintained through turnover, as mature cells are replaced by new ones. This regenerative capacity declines with age through thymic involution. As the thymus shrinks and T cell production wanes, the number and diversity of mTECs also decrease, contributing to a weaker immune system and increased susceptibility to autoimmunity in older individuals.