Transcriptional regulation by AIRE: molecular mechanisms of central tolerance

Abstract

The negative selection of T cells in the thymus is necessary for the maintenance of self tolerance. Thymic medullary epithelial cells have a key function in this process as they express a large number of tissue-specific self antigens that are presented to developing T cells. Mutations in the transcriptional regulator AIRE cause a breakdown of central tolerance associated with decreased expression of self antigens in the thymus. In this Review, we discuss the role of AIRE in the thymus and recent advances in our understanding of how AIRE might function to regulate gene expression.Autoimmunity is caused by the breakdown of mechanisms that maintain immune tolerance to self tissues. Most self-reactive T cells are deleted in the thymus, resulting in central tolerance [G], which is further supported by regulatory mechanisms outside of primary lymphoid tissues, which are collectively known as peripheral tolerance. As the main mechanism of central tolerance, the negative selection [G] of self-reactive thymocytes occurs mainly in the medullary compartment of the thymus 1, 2. The medullary thymic epithelial cells (mTECs) express a large number of genes, including tissue-specific antigens (TSAs, also named tissue-restricted antigens or peripheral tissue antigens) that are normally present only in specialized peripheral organs and are apparently not required for the direct function of mTECs 3, 4. During negative selection, these encoded TSAs are presented by mTECs or dendritic cells to differentiating thymocytes as self antigens5, 6, leading to the Correspondence: Pärt Peterson, PhD, Molecular Pathology, Ravila 19, Biomedicum, University of Tartu, Tartu 50411, Estonia, Phone: +372 7374202, Fax: +372 7374207, part.peterson@ut.ee. Online at-a-glance summary • AIRE is mainly expressed by mature thymic medullary epithelial cells, where it promotes the promiscuous expression of many tissue-specific antigens (TSAs).• TSAs that are upregulated by AIRE are presented to developing thymocytes, and this is required for efficient negative selection. Aberrant negative selection in the absence of AIRE leads to the escape of self-reactive thymocytes to the periphery and subsequent autoimmunity.• AIRE contains several domains that are characteristic of transcriptional regulators and chromatin-binding proteins, such as a CARD, a SAND domain and PHD fingers. Concordantly, many studies have confirmed AIRE's function as a potent transcriptional activator.• Several proteins have been found to interact with AIRE, including CBP, PIAS1, DNA-PK, histone H3 with an unmethylated N-terminus (lysine 4) and P-TEFb.• Interaction with histone H3 that is unmethylated at lysine 4 allows AIRE to bind to certain chromatin regions. At target gene promoters, AIRE promotes transcriptional elongation by binding and recruiting the positive transcription elongation factor b (P-TEFb) complex to RNA polymerase II.• AIRE-regulated genes tend to cluster in the genome; however, recent findings indicate that at a single-cell level, the expression of TSAs varies, ...

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

“…Central tolerance is enforced by the thymic expression of tissue-specific antigens such as myelin proteins in medullary thymic epithelial cells (mTECs) driven by the transcription factor autoimmune regulator. [25][26][27] The expression of peripheral antigens in mTECs results in the depletion of high affinity self-reactive clones and the differentiation of natural Tregs. [27][28][29] Thymic DCs cross-present tissue-specific antigens expressed by mTECs.…”

“…[25][26][27] The expression of peripheral antigens in mTECs results in the depletion of high affinity self-reactive clones and the differentiation of natural Tregs. [27][28][29] Thymic DCs cross-present tissue-specific antigens expressed by mTECs. 30,31 Moreover, peripheral DCs migrate to the thymus where they present peripheral antigens.…”

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

“…Most self-reactive T cells are thought to be deleted in the thymus in a process known as central tolerance. Throughout development, the autoimmune regulator (AIRE) induces the expression of tissue specifi c antigens (TSA) in thymic epithelial cells (Tecs) (Peterson, Org et al 2008). It has been shown that Tecs from the medulla are capable of presenting antigens to immature CD4 + /CD8 + double positive (DP) thymocytes to either enable their commitment to mature naive T cells (positive selection) or their deletion (negative selection) (Gallegos and Bevan 2004;Peterson, Org et al 2008).…”

“…Throughout development, the autoimmune regulator (AIRE) induces the expression of tissue specifi c antigens (TSA) in thymic epithelial cells (Tecs) (Peterson, Org et al 2008). It has been shown that Tecs from the medulla are capable of presenting antigens to immature CD4 + /CD8 + double positive (DP) thymocytes to either enable their commitment to mature naive T cells (positive selection) or their deletion (negative selection) (Gallegos and Bevan 2004;Peterson, Org et al 2008). This process is performed in collaboration with bone marrowderived DCs that are able to capture antigens from medullar Tecs and present them on MHC molecules to DP thymocytes (Gallegos and Bevan 2004).…”

Targeting disease by immunomodulation

“…DCs are central for the establishment of central and peripheral tolerance. [5][6][7] With a focus on multiple sclerosis (MS), Quintana et al 8 discussed how abnormalities in DC function contribute to the pathology of MS and how the therapeutic use of immunomodulatory drugs modulates DC function. The anti-inflammatory role of the cytokine interleukin-27 (IL-27) in DCs is emphasized with regard to therapeutic applicability.…”