The authors have previously shown that the generation of the first mTECs expressing autoimmune regulator (AIRE) in the embryonic thymus involves signals from LTi cells through receptor activator of NF-κB (RANK; also known as TNFRSF11A). But studies of mice that lack LTi cells revealed that other cells can also support initial mTEC development. To investigate this possibility, the authors stained thymus tissue sections at embryonic day 17. They found a striking concentration of thymocytes expressing γδ T cell receptors (γδTCRs) — in particular the Vγ5 TCR — in medullary areas. These Vγ5+ thymocytes are the progenitors of a subset of invariant intraepithelial lymphocytes known as dendritic epidermal T cells (DETCs). Confocal microscopy analyses confirmed the combined presence of LTi cells and Vγ5+ thymocytes in medullary areas. To explore their functional relevance, the authors studied reaggregate thymus organ cultures of fetal thymus lobes supplemented with Vγ5+ thymocytes or LTi cells. Vγ5+ thymocytes were as efficient as LTi cells at supporting the development of mature AIRE+ mTECs and, importantly, this was abrogated by inhibition of RANK–RANK ligand (RANKL) interactions. Accordingly, both immature (CD45RBlow) and mature (CD45RBhi) Vγ5+ thymocytes were shown to express RANKL, albeit at much lower levels than LTi cells.
The interaction between mTECs and Vγ5+ thymocytes is reciprocal, as mature AIRE+ mTECs were shown to express SKINT1, which is essential for the selection and generation of DETCs. To further investigate the link between AIRE+ mTECs and Vγ5+ DETCs, the authors studied embryos with impaired RANK signalling. Embryonic thymi from mice lacking RANK or the nuclear factor-κB (NF-κB) component RELB lacked AIRE+ mTECs and had a marked reduction in mature DETCs compared with wild-type controls. This suggests that efficient maturation of Vγ5+ thymocytes depends on RANK signalling as well as on SKINT1. Interestingly, DETC maturation did not seem to require AIRE expression by the mTECs, as it proceeded normally in Aire−/− mice.
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