Abstract
Thymic epithelial cells (TECs) provide the microenvironment required for the development of T cells in the thymus. A unique property of medullary thymic epithelial cells (mTECs) is their expression of a wide range of tissue-restricted self-antigens, critically regulated by the nuclear protein AIRE, which contributes to the selection of the self-tolerant T cell repertoire, thereby suppressing the onset of autoimmune diseases. The TNF receptor family (TNFRF) protein receptor activator of NF-κB (RANK), CD40 and lymphotoxin β receptor (LtβR) regulate the development and functions of mTECs. The engagement of these receptors with their specific ligands results in the activation of the NF-κB family of transcription factors. Two NF-κB activation pathways, the classical and non-classical pathways, promote the development of mature mTECs induced by these receptors. Consistently, TNF receptor-associated factor (TRAF6), the signal transducer of the classical pathway, and NF-κB inducing kinase (NIK), the signal transducer of the non-classical pathway, are essential for the development of mature mTECs. This review summarizes the current understanding of how the signaling by the TNF receptor family controls the development and functions of mTEC.
Highlights
The development of self-tolerant T cells and regulatory T cells in the thymus requires a microenvironment of both nonhematopoietic stroma cells and cells of hematopoietic origin (Gill et al, 2003; Takahama, 2006; Anderson and Takahama, 2012)
We primarily focus on the role of signaling by the TNF receptor family (TNFRF) members RANK, CD40, and lymphotoxin β receptor (LtβR) in the development and functions of medullary thymic epithelial cells (mTECs) in the establishment of self-tolerance
Several studies have provided evidence that RANK, CD40, and LtβR signaling are critical for the development of mTECs
Summary
The development of self-tolerant T cells and regulatory T cells in the thymus requires a microenvironment of both nonhematopoietic stroma cells and cells of hematopoietic origin (Gill et al, 2003; Takahama, 2006; Anderson and Takahama, 2012). IL-7 and Delta-like 4 expressed by TECs promote their proliferation and commitment to the T-cell lineage, thereby leading to the differentiation of CD4+CD8+ double-positive (DP) T cells expressing a diverse repertoire of T-cell antigen receptors (TCRs) (Hozumi et al, 2008; Koch et al, 2008; Hong et al, 2012) This T-cell repertoire is scrutinized by the TECs displaying the complex of self-peptides and MHC molecules (self-pMHCs) (Kyewski and Klein, 2006; Anderson et al, 2007; Klein et al, 2009). It is important future study to clarify the relative contributions of mTECs and cDCs to negative selection
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