T cells are a type of white blood cell and a component of the adaptive immune system, providing targeted defense against specific pathogens. These cells must distinguish between the body’s own healthy tissues and foreign invaders to identify and eliminate infected cells. The immune system’s ability to avoid attacking itself is known as immune tolerance, a balance that ensures T cells are directed only at legitimate threats.
The Thymus as the T-Cell Training Ground
The primary organ where T cells mature is the thymus, a small gland located in the chest behind the sternum. Immature T cells, known as thymocytes, originate from stem cells in the bone marrow and travel to the thymus. This organ functions as a training ground where thymocytes undergo a selection process to ensure they are both functional and safe. The thymus is composed of two main areas: an outer region called the cortex and a central region called the medulla, which are the sites for different stages of T cell maturation.
The Process of Negative Selection
Negative selection is the process that removes self-reactive T cells, and it primarily takes place in the medulla of the thymus. After thymocytes pass an initial functionality check, they migrate from the cortex into the medulla. In this region, they are exposed to a wide array of self-antigens, which are proteins and peptides representative of tissues from all over the body. This exposure is orchestrated by medullary thymic epithelial cells (mTECs).
These specialized mTECs can produce proteins that are typically found in other organs, such as the pancreas, liver, or skin. This is made possible by a protein called the Autoimmune Regulator (AIRE), which activates the expression of thousands of these tissue-specific antigens. By presenting this diverse library of self-peptides, the thymus can test developing T cells against a comprehensive sample of the body’s own components.
The outcome of this test is determined by the strength of the interaction between a T cell’s receptor and the self-antigens it encounters. If a thymocyte’s receptor binds too strongly to a self-antigen, it is identified as a potential danger to the body’s tissues. Such a high-affinity interaction triggers programmed cell death, or apoptosis, which eliminates the self-reactive T cell. This process ensures that T cells with the potential to cause autoimmune damage are destroyed before they complete maturation.
The Role of Positive Selection
Before T cells undergo negative selection, they must first pass through positive selection, which occurs in the thymic cortex. The purpose of this step is to determine if the T cells are functional. In the cortex, thymocytes are tested on their ability to recognize the body’s own major histocompatibility complex (MHC) molecules. These proteins are on the surface of other cells and act as platforms for presenting antigens.
During positive selection, cortical thymic epithelial cells present self-peptides on MHC molecules. Developing T cells must demonstrate that their receptors can bind to these MHC-peptide complexes with at least a weak affinity. T cells unable to recognize MHC molecules are considered non-functional and are instructed to die by “death by neglect.” Only the thymocytes that successfully recognize self-MHC molecules survive and migrate to the medulla for negative selection.
Consequences of Failed Negative Selection
The process of negative selection is not infallible, and occasionally, self-reactive T cells evade destruction and escape into the circulatory system. When this occurs, these T cells can travel throughout the body and encounter the self-antigens they are programmed to recognize on healthy tissues. Upon recognizing these antigens, the T cells can initiate an inflammatory attack, leading to the development of autoimmune diseases.
The specific disease that develops depends on which tissues are targeted by the escaped T cells. For example, if T cells that react to proteins in the pancreas survive selection, they can destroy the insulin-producing beta cells, leading to Type 1 diabetes. If T cells recognizing components of the myelin sheath escape, they can cause the neurological damage characteristic of multiple sclerosis.