Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.
Bottom Line: The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance.In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire.Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.
Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.Show MeSH
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Mentions: To investigate whether the importance of Rank-dependent Aire+ mTEC development for Skint-1-mediated DETC maturation is directly dependent upon Aire itself, we analyzed Skint1 expression and the emergence of epidermal Vγ5+ DETCs in neonatal Aire-deficient mice. We found that in contrast to the known Aire dependency of genes such as Spt1 (salivary protein 1) (Figure 7A), Skint1 expression was unaltered in Aire−/− neonatal thymus (Figure 7A). In line with this lack of requirement for Aire in the expression of Skint1, comparison of the neonatal epidermis of Aire−/− and WT mice showed no changes in the frequency of epidermal CD3+ cells (Figure 7B), including those expressing Vγ5+ (Figures 7C and 7D). Thus, despite the association between the maturation of Aire+ mTECs and invariant Vγ5TCR+ DETC maturation, Aire deficiency does not impair the emergence of an invariant Skint-1-dependent DETC pool.
Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.