Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases

Abstract

Elimination of potential self-reactive T cells in the thymus is crucial for preventing the onset of autoimmune diseases. Epithelial cell subsets localized in thymic medulla [medullary thymic epithelial cells (mTECs)] contribute to this process by supplying a wide range of self-antigens that are otherwise expressed in a tissue-specific manner (TSAs). Expression of some TSAs in mTECs is controlled by the autoimmune regulator (AIRE) protein, of which dysfunctional mutations are the causative factor of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In addition to the elimination of self-reactive T cells, recent studies indicated roles of mTECs in the development of Foxp3-positive regulatory T cells, which suppress autoimmunity and excess immune reactions in peripheral tissues. The TNF family cytokines, RANK ligand, CD40 ligand, and lymphotoxin were found to promote the differentiation of AIRE- and TSA-expressing mTECs. Furthermore, activation of NF-κB is essential for mTEC differentiation. In this mini-review, we focus on molecular mechanisms that regulate induction of AIRE and TSA expression and discuss possible contributions of these mechanisms to prevent the onset of autoimmune diseases.

Keywords: NF-κB; TNF receptor family; autoimmune disease; gene expression; medullary thymic epithelial cells.

Figure 1

Proposed model for differentiation of mTECs. Both mTECs and cTECs are generated from a bi-potent progenitor in the fetal and adult thymus. mTECs are classified by expression of MHC class II (MHC II), CD80, AIRE, and involucrin. mTECs expressing low levels of MHC II and CD80 are considered immature and give rise to mature mTECs, expressing high levels of MHC II and CD80, and a more diverse set of tissue-specific antigens (TSAs). MHC II-high and CD80-high mature mTECs are further separated into AIRE-positive and AIRE-negative subpopulations. AIRE-positive mature mTECs are postmitotic and undergo apoptosis or otherwise differentiate into involucrin-positive mTECs.

Figure 2

NF-κB activation pathways triggered by TNF family signaling. Interaction of TNF family ligand (RANK ligand, CD40 ligand, and lymphotoxin α and β complex) with their respective receptors (RANK, CD40, and LtβR) induces activation of NF-κB pathways. Interaction between the ligand and its receptor induce the binding of TRAF-family proteins to the cytoplasmic domains of TNF receptors. TRAF-family proteins in turn activate downstream serine/threonine kinase cascade. These kinases trigger the degradation of inhibitory proteins that sequester NF-κB in cytosol, thereby leading to the translocation and transcriptional activation of NF-κB members. NF-κB pathways are classified into classical and non-classical pathway. In the non-classical pathway, NF-κB complex consisting of RelB and p52 is activated. NIK is critical for the non-classical NF-κB pathway. TRAF6, a member of the TRAF protein family, was reported to regulate only the classical NF-κB pathway, which causes nuclear translocation of mainly the RelA complex. On the other hand, other TRAF members function in the non-classical NF-κB pathway by binding to the TNF family receptors.