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Self-representation in the thymus: an extended view
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Journal Article
Self-representation in the thymus: an extended view
2004
Overview
Key Points
Self-tolerance of T cells is commonly divided into central (thymic) and peripheral tolerance according to its site of induction. Self-tolerance to most peripheral parenchymal organs has been ascribed to peripheral tolerance. The finding that many tissue-specific genes are expressed by medullary thymic epithelial cells (mTECs) — known as promiscuous gene expression — has changed this view.
Tissue-specific self-antigens expressed by mTECs are functionally and structurally highly diverse and encompass essentially all organs. This allows self-antigens, which are expressed in a spatially or temporally restricted manner (such as pregnancy- or puberty-associated self-antigens) to become continuously accessible to developing T cells.
mTECs express self-antigens of both large and small organs at similar frequencies, therefore equating possible differences in the tolerogenic potential of organs of varying size.
Both genetic and epigenetic mechanisms seem to account for this unorthodox mode of gene expression.
Deficiencies in promiscuous gene expression can lead to organ-specific or multi-organ autoimmune syndromes.
Promiscuous gene expression might have co-evolved with adaptive immunity in the wake of antigen-receptor diversity early during vertebrate development.
The thymus has been viewed as the main site of tolerance induction to self-antigens that are specifically expressed by thymic cells and abundant blood-borne self-antigens, whereas tolerance to tissue-restricted self-antigens has been ascribed to extrathymic (peripheral) tolerance mechanisms. However, the phenomenon of promiscuous expression of tissue-restricted self-antigens by medullary thymic epithelial cells has led to a reassessment of the role of central T-cell tolerance in preventing organ-specific autoimmunity. Recent evidence indicates that both genetic and epigenetic mechanisms account for this unorthodox mode of gene expression. As we discuss here, these new insights have implications for our understanding of self-tolerance in humans, its breakdown in autoimmune diseases and the significance of this tolerance mode in vertebrate evolution.
Publisher
Nature Publishing Group UK,Nature Publishing Group
