The Role of the Thymus in the Control of Autoimmunity (original) (raw)
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Central Self - Tolerance by Thymic Presentation of Self - Antigens and Autoimmunity
Current Medicinal Chemistry-Immunology, Endocrine & Metabolic Agents, 2001
Before reacting against non-self infectious agents, the immune system is educated to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during fetal ontogeny (central tolerance) and also involves inactivating mechanisms outside the thymus (peripheral tolerance). The thymus is the primary lymphoid organ implicated in the development of competent and self-tolerant T cells. During ontogeny, T cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, and then bone marrow) enter the thymus and undergo a program of proliferation, T cell receptor (TCR) gene rearrangement, maturation and selection. Close interactions between thymocytes (pre-T cells) and the thymic cellular environment are crucial both for T cell development and induction of central self-tolerance. Thymic epithelial and stromal cells synthesize polypeptides belonging to various neuroendocrine families. The thymic repertoire of neuroendocrine-related precursors transposes at the molecular level the dual role of the thymus in T cell negative and positive selection. Thymic precursors not only constitute a source of growth peptides for cryptocrine signaling between thymic stromal cells and pre-T cells, but are also processed in a way that leads to the presentation of self-antigens by thymic major histocompatibility complex (MHC) proteins. Thymic neuroendocrine self-antigens often correspond to peptide sequences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens is not restricted by MHC alleles. Following the presentation of neuroendocrine self-antigens by thymic MHC proteins, the T cell system might be educated to tolerate main hormone families. Recent experiments argue that a defect in the thymic essential tolerogenic function is implicated as an important factor in the pathophysiology of many autoimmune diseases.
The thymus in 2013: from a 'vestigial' organ to immunological self-tolerance and autoimmunity
Proceedings of the Belgian Royal Academies of Medicine, 2014
The programming of 'neuroendocrine self' occurs in the thymus, a cross-talk organ the emergence of which some 450 millions years ago allowed an integrated and harmonious coevolution between the major systems of cell-to-cell communication, the nervous, endocrine and immune systems. Neuroendocrine self-peptides are secreted by thymic epithelial cells not according to the classic model of neurosecretion, but are processed for the presentation by, or in association with, the major histocompatibility complex proteins. The autoimmune regulator (Aire) gene/protein controls the transcription of neuroendocrine genes in thymic epithelial cells. The presentation of self-peptides derived from endogenous proteins in the thymus is responsible for the negative selection of self-reactive T cells and, paradoxically in the same time, for the positive selection of thymodependant regulatory T (tTreg) cells that can inhibit, in the periphery, those self-reactive T cells that escaped clonal deletion in the thymus. The development of autoimmunity towards endocrine glands first results from a defect in the intrathymic programming of self-tolerance to neuroendocrine functions. This defect may be genetic or acquired, for example during an enteroviral infection. This novel knowledge of normal and pathological functions of the thymus constitutes a solid basis for the development of a novel type of tolerogenic/negative 'self-vaccination' against type 1 diabetes.
Selection and fine-tuning of the autoimmune T-cell repertoire
Nature Reviews Immunology, 2002
The immune system must avoid aggressive T-cell responses against self-antigens. But, paradoxically, exposure to self-peptides seems to have an important role in positive selection in the thymus and the maintenance of a broad T-cell repertoire in the periphery. Recent experiments have highlighted situations that allow high-avidity self-reactive T cells to avoid negative selection in the thymus. Accumulating evidence indicates that
The Journal of Immunology, 2002
T cell tolerance to self Ags is in part established in the thymus by induction of apoptosis or anergy of potentially autoreactive thymocytes. Some autospecific T cells nevertheless migrate to peripheral lymphoid organs but are kept under control by the recently identified CD4 ؉ CD25 ؉ regulatory T cell subset. Because these cells inhibit autoimmunity more efficiently than useful non-self Ag-specific immune responses, they are probably autospecific, posing important questions as to how they develop in the thymus. In this study we show that significantly more peripheral CD4 ؉ CD25 ؉ regulatory T cells recognize self than non-self Ags. However, we also show for a large panel of endogenous superantigens as well as for self peptide/MHC complexes that autospecific CD4 ؉ CD25 ؉ thymocyte precursors are normally deleted during ontogeny. Combined, our data firmly establish that the repertoire of regulatory T cells is specifically enriched in autospecific cells despite the fact that their precursors are normally susceptible to thymic deletion.