The body’s defense system relies on specialized white blood cells called T cells to protect against threats. These cells are a central part of the adaptive immune system, which builds tailored defenses against specific invaders. T cells are responsible for recognizing and eliminating infected cells, abnormal cells like cancer cells, and foreign pathogens such as viruses, bacteria, fungi, and parasites. They achieve this by identifying specific molecular fragments, known as antigens, which mark these harmful entities.
The Purpose of T Cell Education
Before T cells can protect the body, they undergo a training process within the thymus, an organ located between the lungs. This “education” ensures that T cells can distinguish between the body’s own healthy components (“self”) and external threats (“non-self”). Without this discrimination, the immune system could mistakenly attack healthy tissues.
Immature T cells, originating from stem cells in the bone marrow, migrate to the thymus to mature. During development, each T cell generates a unique T cell receptor (TCR), a protein on its surface designed to recognize specific antigens. This maturation involves two main stages: positive selection and negative selection. Positive selection ensures that T cells can recognize major histocompatibility complex (MHC) molecules, which are proteins on cell surfaces that present antigens.
Negative Selection: Preventing Self-Attack
Negative selection is a stage where T cells that react too strongly to the body’s own self-antigens are eliminated. This process takes place in the thymus, particularly in the medulla. Its purpose is to prevent the release of self-reactive T cells into the bloodstream, which could lead to autoimmune diseases.
During negative selection, thymic antigen-presenting cells (APCs) display a wide array of self-antigens on MHC molecules. Immature T cells interact with these presented self-antigens via their TCRs. If a T cell’s TCR binds too strongly to a self-antigen presented by an MHC molecule, it receives signals to undergo apoptosis, which is programmed cell death. This strong binding indicates the T cell is self-reactive and poses a risk of attacking the body’s own tissues.
The Autoimmune Regulator (AIRE) gene plays a role in this process by enabling thymic medullary epithelial cells to express a broad spectrum of tissue-restricted antigens (TRAs). These TRAs are found in peripheral tissues, and their presentation in the thymus allows developing T cells to be exposed to a diverse set of self-antigens. This comprehensive exposure helps ensure potentially self-reactive T cells are identified and removed.
Some self-reactive T cells that receive strong TCR stimulation during negative selection may not undergo apoptosis but are steered towards becoming regulatory T cells (Tregs). These specialized T cells help maintain immune tolerance by suppressing immune responses and preventing the immune system from attacking healthy cells in the periphery. This dual outcome of either elimination or conversion to Tregs is a mechanism to maintain self-tolerance.
Consequences of Impaired Negative Selection
When the negative selection process is compromised, self-reactive T cells can escape the thymus and enter the bloodstream. These unchecked T cells then mistakenly identify healthy tissues as foreign invaders. This loss of self-tolerance can lead to autoimmune diseases.
In autoimmune conditions, the immune system attacks its own tissues, causing chronic inflammation and widespread tissue damage. Examples of autoimmune diseases that can arise from failures in negative selection include systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes. Defects in negative selection have been observed in autoimmune diabetes. The presence of self-reactive T cells in the periphery, which should have been deleted, is a hallmark of these conditions.