The presentation of neuroendocrine self-peptides in the thymus: An essential event for individual life and vertebrate survival

Confirming Burnet’s early hypothesis, elimination of self-reactive T cells in the thymus was demonstrated in the late 80’s and an important question immediately arose about the nature of the immune self expressed in the thymus. Many genes encoding neuroendocrine-related and tissue-restricted antigens (TRAs) are transcribed in thymic epithelial cells (TECs). They are then processed for presentation by proteins of the major histocompatibility complex (MHC) expressed by TECs and thymic dendritic cells (DCs). MHC presentation of self-peptides in the thymus programs self-tolerance by two complementary mechanisms: 1° Negative selection of self-reactive ‘forbidden’ T-cell clones starting already in fetal life, and 2° generation of self-specific thymic T regulatory (tTreg) cells, mainly after birth. Many studies, including the discovery of the AutoImmune REgulator (AIRE) and fasciculation and elongation protein zeta family zinc finger (FEZF2) proteins, have shown that a defect in thymus central self-tolerance is the earliest event promoting autoimmunity. AIRE and FEZF2 control the level of transcription of many neuroendocrine self-peptides and TRAs in thymic epithelium. Furthermore, Aire and Fezf2 mutations are associated with development of autoimmunity in peripheral organs. The discovery of the intrathymic presentation of self-peptides has revolutionized our knowledge of immunology and is opening novel avenues for prevention/treatment of autoimmunity.