Thymic Epithelial Cell Development and Its Dysfunction in Human Diseases

Figure 2

The effects and signaling pathways of TNFRs on TECs. Tumor necrosis factor receptor (TNFR) including the receptor activator for NFκB (RANK), CD40, and lymphotoxin β receptor (LTβR) signalings is especially important for mTEC formation and development. In the embryonic thymus, RANKL is provided by CD4⁺CD3⁻ lymphoid tissue inducer (LTi) cells and Invariant Vγ5⁺ dendritic epidermal T cells, while in the postnatal thymus, RANKL, CD40L, and LTβR ligands LTα, LTβ, and LIGHT are provided exlusively by positively selected mature T cells. Canonical and noncanonical NF-κB signal pathways are the major downstream of RANK, CD40, and LTβR. In classical NF-κB pathways, TNFR-associated factor 6 (TRAF6) activates TGF-β activating kinase 1 (TAK1), which in turn activates the IKK complex composed of IKKα, IKKβ, and NEMO. The IKK complex phosphorylates IkBα for degradation, leading to translocation of the RelA/p50 complex to the nucleus. Nonclassical NF-κB pathways activate p52/RelB via TRAF2/5. IKKα is phosphorylated by NIK, which in turn triggers p100 partial degradation to p52 and then translocation to the nucleus together with RelB.