T cells distinguish self from nonself by reading short peptide fragments displayed on the surface of other cells and integrating that information with co-receptor signals and environmental context. The T cell receptor binds a peptide only when it is presented by a matching major histocompatibility complex molecule, a principle of MHC restriction demonstrated by Peter Doherty University of Melbourne and colleagues. This biochemical lock-and-key recognition gives T cells the specificity to detect infected or transformed cells while ignoring ordinary cellular proteins when tolerance mechanisms are intact.
Positive and negative selection in the thymus
Developing T cells transit the thymus where two complementary filtering steps shape the repertoire. Positive selection favors cells that can weakly recognize self-MHC so they can function in the body, while negative selection deletes or diverts strongly self-reactive cells to prevent autoimmunity. Medullary thymic epithelial cells express a wide variety of tissue-restricted proteins through the action of the autoimmune regulator AIRE so that potentially dangerous clones are exposed to many self-antigens and removed. NIAID staff at the National Institute of Allergy and Infectious Diseases describes these thymic checkpoints as central to establishing self-tolerance.
Peripheral tolerance and its limits
Some self-reactive T cells escape the thymus, so peripheral safeguards enforce tolerance in tissues. Regulatory T cells suppress inappropriate responses, anergy renders unhelpful clones inactive, and controlled deletion removes persistent threats. Shimon Sakaguchi Osaka University provided foundational work identifying regulatory T cells as essential moderators of peripheral immune balance. Environmental events such as infections can subvert these safeguards by providing inflammatory signals or molecular mimicry that make self-peptides appear dangerous, a mechanism highlighted by the Centers for Disease Control and Prevention in explanations of postinfectious autoimmunity.
Consequences, relevance and human dimensions
The balance between recognition and tolerance is central to human health and society. When it fails, autoimmune diseases can produce chronic disability and show distinct demographic patterns with higher prevalence among women as documented by the National Institutes of Health. In transplantation, matching MHC and controlling T cell activation remain critical to graft survival. Conversely, modern cancer therapies deliberately break some tolerance barriers to unleash T cells against tumors, a strategy advanced by James Allison MD Anderson Cancer Center that transformed outcomes for many patients. Understanding how T cells distinguish self from nonself therefore links molecular mechanisms in the thymus to clinical practice, public health patterns and cultural challenges around care and allocation of therapies.
