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 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 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.

Keywords: autoimmunity; reverse; self-peptide; self-tolerance; self-vaccine; thymus; tolerogenic.

Figure 1

The triple role of thymic neuroendocrine self‐peptides in T cell differentiation. Following its transcription under AIRE (or FEZF2) control in TEC, a neuroendocrine precursor X is processed according to two distinct pathways. On the one hand, it is the source of a cryptocrine ligand X that is able to bind to a neuroendocrine cognate receptor expressed by T cells, to mobilize second messengers (such as IP3), and to induce intracellular events (such as phosphorylation of the focal adhesion‐related kinases p125^Fak and p130^Cas for thymic OT). This constitutes a positive accessory signal during T cell development. On the other hand, the same precursor X is also processed as the source of self‐peptide(s) X that is presented by MHC proteins of TECs or after transfer to thymic DCs. During fetal life, self‐presentation induces negative selection of T cells that are randomly bearing a TCR specific of this MHC−self‐peptide X complex. Mainly after birth, self‐presentation also promotes the generation of tT_reg cells specific to the same complex. The electron microscopy photograph is a generous gift from Martin Wiemann, now at the University of Duisburg‐Essen.

Figure 2

Role of the thymus in programming central self‐tolerance and in the development of autoimmunity. In normal conditions, under the control of AIRE and FEZF2, TECs express numerous genes related to neuroendocrine families or encoding TRAs. MHC presentation of these self‐peptides induces T cell differentiation, negative selection of self‐reactive T cells, and generation of tT_reg cells with the same specificity. In pathological conditions, the decrease in intrathymic expression and presentation of self‐peptides leads to continuous generation in the blood of self‐reactive “forbidden” T cells (T_eff cells), as well as to a decrease in the generation of self‐specific tT_reg cells. This is a condition, necessary but not sufficient, for the development of an autoimmune response against target antigens. For the clinical manifestations of an autoimmune disease, the intervention of environmental factors is also requested.

Figure 3

Integrated evolution of the immune and neuroendocrine systems. Neuroendocrine precursors did not evolve extensively except by gene duplication and differential RNA splicing. Throughout evolution, the neuroendocrine and innate immune system have evolved in parallel, and still coexist in all living species without any aggression of the innate immune system toward neuroendocrine glands. A high risk of inherent autoimmunity toward neuroendocrine tissues resulted from the appearance of recombination‐activating genes RAG1 and RAG2, and RAG‐dependent adaptive immunity in jawed cartilaginous fishes some 450 million years ago. Preceded by ancestor paralog Foxn4‐expressing thymoids in gill baskets of lamprey larvae, the first unique thymus (with Foxn1‐expressing TECs) also emerged in jawed vertebrates. The intrathymic presentation of dominant neuroendocrine self‐peptides (arrows) may be viewed a posteriori as a very efficient and economical way to instruct the adaptive T cell system in recognizing and tolerizing neuroendocrine families already during thymus‐dependent T cell differentiation in fetal life. VCBP, variable region‐containing chitin‐binding protein; VLR, variable lymphocyte receptor.

Figure 4

Classical vaccination and the concept of “reverse” self‐vaccination. Classical vaccination essentially relies on an immunogenic response (naive T cell activation and induction of memory immune cells) elicited by administration of antigen(s) representative of pathogens. T1D pathogenesis also relies on an immunogenic response targeting several T1D antigens, such as insulin as the primary T1D autoantigen (X). The novel type of “reverse” self‐vaccination proposes to use thymus self‐peptides for promoting a tolerogenic response (deletion of self‐reactive T cells and generation of self‐reactive T_reg cells). For T1D prevention and cure, the corresponding thymus self‐peptide is IGF‐2 (X′). Noteworthy, insulin is actually an “altered self” peptide of IGF‐2.101 ⁻ 103