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: Given that RelB is downstream of multiple, TNFSF-R family members, we next analyzed by flow cytometry thymocyte suspensions obtained from neonatal Tnfrsf11a−/− mice. Again, we found a dramatic reduction in the frequency of cells expressing high levels of both the Vγ5TCR and CD45RB (Figures 5A–5C), which resulted in a skewing in the mature:immature DETC ratio in Tnfrsf11a−/− mice (1:100) as compared to WT littermate controls (1:3) (Figure 5D). In addition, analysis of neonatal epidermal preparations showed that Tnfrsf11a−/− mice have a dramatic reduction in the frequency of total epidermal CD3+ T cells (Figure 6A), as well as a disproportionate reduction in those expressing the Vγ5TCR (Figures 6B and 6C). Further flow cytometric analysis with an antibody that detects the Vγ5Vδ1 γδTCR (clone 17D1) showed that the small numbers of Vγ5+ DETCs present in Tnfrsf11a−/− mice epidermis were also Vδ1+, suggesting that residual levels of Skint1 detected in the absence of Rank may still support the generation of small numbers of invariant DETCs. Nevertheless, the combined data on Tnfrsf11a−/− mice, demonstrating a defect in intrathymic Vγ5+ thymocyte maturation, coupled to diminished numbers of Vγ5+ DETCs, demonstrate that efficient maturation of an invariant Vγ5TCR+ DETC repertoire depends upon expression of the TNFSF-Receptor Rank, just as it depends on Skint-1 (Barbee et al., 2011; Lewis et al., 2006).
Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.