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 study the potential link between Aire+ mTECs and Vγ5+ DETC progenitors, we initially studied the embryonic thymus of Relb−/− mice, a transcription factor in the alternative NF-κB signaling pathway that is downstream of several TNFSF-R family members including CD40 and Rank, known regulators of mTEC maturation. Consistent with this, and as previously reported, Aire+ mTECs were absent from the thymus of E17 Relb−/− embryos (data not shown). When we analyzed Vγ5+ thymocyte development, with upregulation of CD45RB as a marker of maturation (Lewis et al., 2006), we found a statistically significant decrease in both CD45RBlo and CD45RBhi subsets in Relb−/− embryonic thymuses compared to WT controls (Figures 4A and 4B). Despite a reduction in both CD45RB subsets, a dramatic skewing in the ratio (approximately 6:1) of WT:Relb−/− CD45RBhi cells was observed, compared to a ratio of 1.6:1 for WT:Relb CD45RBlo cells, suggesting that although RelB may play a subtle role in the initial emergence of Vγ5CD45RBlo cells, it appears critically important in the maturation to the Vγ5+CD45RBhi stage.
Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.