The immune system must distinguish between foreign invaders (“non-self”) and the body’s own tissues (“self”). This capacity is the foundation of healthy immunity; without it, the body would attack itself, leading to serious disease. The necessary state of immunological peace with the body’s own cells is called self-tolerance.
Achieving self-tolerance requires an active quality control system during immune cell development. This system is managed by negative selection, which systematically eliminates potentially dangerous immune cells. Negative selection ensures that the randomly generated immune receptors, designed to detect countless pathogens, are cleansed of components that react too strongly with the body’s own structures before the cells enter circulation.
The Central Immune Screening Mechanism
T-cell development involves a stringent education process within the thymus, an organ located in the chest. T-cell precursors migrate there and randomly rearrange their T-cell receptor (TCR) genes, creating diverse threat detectors. This process inevitably produces many receptors highly reactive to the body’s own proteins.
Immature T-cells, called thymocytes, enter the thymic medulla where specialized local cells orchestrate negative selection. Medullary thymic epithelial cells (mTECs) regulate this screening by presenting self-antigens. This presentation is enabled by the Autoimmune Regulator (AIRE) protein.
AIRE forces mTECs to express tissue-restricted antigens (TRAs), which are normally found only in distant organs like the pancreas or liver. This “promiscuous gene expression” creates a comprehensive library of self-markers within the thymus. TRAs are presented on Major Histocompatibility Complex (MHC) molecules, allowing thymocytes to test their receptors against the body’s proteome.
The strength of the interaction determines the cell’s fate. If a thymocyte receptor binds too strongly to the self-antigen, the cell is deemed highly self-reactive and receives a signal for programmed cell death (apoptosis). This elimination of dangerous clones is called clonal deletion.
Only thymocytes showing weak or intermediate affinity for self-antigens are permitted to survive, mature, and exit the thymus. A small fraction of self-reactive thymocytes that survive deletion are diverted into becoming regulatory T-cells (Tregs). These cells mature into components that actively suppress immune responses in the periphery, providing an additional safeguard. This two-part process of deletion and diversion is the primary mechanism for establishing central self-tolerance.
Establishing Systemic Self-Tolerance
The tolerance mechanisms established during T-cell development in the thymus are known as central tolerance. Since central screening cannot test for every possible self-protein, a parallel system called peripheral tolerance exists to manage self-reactive cells that escape elimination. Peripheral tolerance relies on two main strategies to neutralize self-reactive T-cells that enter circulation.
Anergy Induction
The first strategy is anergy, which renders the T-cell functionally unresponsive. Full T-cell activation requires two distinct signals: receptor binding to an antigen and a co-stimulatory signal from the antigen-presenting cell. If a self-reactive T-cell encounters its self-antigen in a non-inflammatory context, the antigen-presenting cell provides only the first signal, withholding the necessary co-stimulatory signal. This incomplete activation causes the T-cell to enter anergy, making it incapable of mounting a destructive response. The cell becomes paralyzed and unable to perform its effector functions.
Active Suppression by Regulatory T-cells (Tregs)
The second strategy involves regulatory T-cells (Tregs) diverted during central screening. These cells actively suppress the activation and proliferation of other T-cells attempting a self-directed attack. Tregs utilize multiple mechanisms to control effector T-cells. One method is the secretion of inhibitory cytokines, such as Interleukin-10 (IL-10) and Transforming Growth Factor-beta (TGF-β), which dampen the inflammatory response. Tregs also suppress through metabolic interference. They express high levels of the Interleukin-2 (IL-2) receptor (CD25), allowing them to consume the local IL-2 supply. Since IL-2 is necessary for other T-cells to proliferate, depleting it effectively prevents the expansion of self-reactive cells.
When the Selection Process Fails
The system of central and peripheral tolerance is robust, but imperfections can allow self-reactive lymphocytes to escape. This failure, known as “leaky” selection, is the root cause of autoimmune disease. When self-reactive T-cells and B-cells enter circulation, they attack normal tissues, causing chronic inflammation and damage.
Type 1 Diabetes
In Type 1 Diabetes, the failure of self-tolerance results in the immune system targeting the insulin-producing beta cells in the pancreas. Autoreactive T-cells destroy these cells after recognizing self-antigens such as Glutamic Acid Decarboxylase (GAD65) and pro-insulin. This targeted destruction eliminates the body’s ability to produce insulin, which is necessary for glucose regulation.
Rheumatoid Arthritis (RA)
A different failure mechanism is observed in Rheumatoid Arthritis (RA), where the immune attack is often directed against post-translationally modified proteins. The immune system recognizes proteins in the joints that have been chemically altered through citrullination. This error leads to the production of anti-citrullinated protein antibodies (ACPA) and autoreactive T-cells that drive inflammation and progressive destruction of cartilage and bone.
Multiple Sclerosis (MS)
In Multiple Sclerosis (MS), the immune system mistakenly attacks the central nervous system. This leads to the destruction of the myelin sheath that insulates nerve fibers, disrupting communication between the brain and the body. The autoreactive T-cells in MS primarily target myelin components, including Myelin Basic Protein (MBP) and Myelin Oligodendrocyte Glycoprotein (MOG).