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

Abstract

Confirming Burnet's early hypothesis, elimination of self-reactive T cells in the thymus was demonstrated in the late 1980s, and an important question immediately arose about the nature of the self-peptides 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. 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 regulatory T lymphocytes (tT reg cells), mainly after birth. Many studies, including the discovery of the transcription factors autoimmune regulator (AIRE) and fasciculation and elongation protein zeta family zinc finger (FEZF2), have shown that a defect in thymus centralself-tolerance is the earliest event promoting autoimmunity. AIRE and FEZF2 control the level of transcription of many neuroendocrine self-peptides and TRAs in the thymic epithelium. Furthermore, AIRE and FEZF2 mutations are associated with the 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.

Modulation of IGF2 Expression in the Murine Thymus and Thymic Epithelial Cells Following Coxsackievirus-B4 Infection

“…This process plays an essential role in the central self-tolerance to neuroendocrine functions. Indeed, a defect in this process (e.g., loss of insulin expression) is the earliest event in the pathogenesis of autoimmune diseases such as type 1 diabetes (T1D) [ 1 ].…”

Primary Immunodeficiency with Severe Multi-Organ Immune Dysregulation

“…AIRE regulates the expression of these tissue-specific genes and TRAs [3,4]. High affinity T-cell receptor (TCR) interactions with MHC-presented self-antigens in the thymic tissue either induce the deletion of thymocytes by apoptosis or shi the T cells into regulatory T cell (Treg) development, thereby preventing autoimmunity [5,6].…”

Regulatory peptides and systems biology: A new era of translational and reverse‐translational neuroendocrinology

“…Thus, it is not surprising that the peptides we refer to as ‘neuroendocrine regulatory peptides’ have additional roles outside of the realm of what we have chosen to call ‘neuroendocrinology’. Examples include the roles of vasopressin and oxytocin in the thymus during self‐tolerance, 74,75 roles of chromogranin peptides in autoimmune defense and disease, 76 and the role of PACAP in vascular and neural inflammation via elaboration by antigen‐presenting cells including microglia and monocyte/macrophages 77‐79 . In the future, we are likely to find, that these functions, appearing now to stand alone from neuroendocrinology as generally construed, are also intimately involved in neuroendocrine regulation.…”