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: Intrathymic development of invariant Vγ5+ thymocyte progenitors and the generation of an invariant Vγ5+ DETC population in the epidermis depends upon thymic stromal cell expression of Skint-1, an Ig superfamily member expressed by mTECs (Lewis et al., 2006). To investigate the possible link between this thymic stromal cell expression of Skint-1, the medullary accumulation of Vγ5+ thymocytes, and Aire+ mTEC development, we further analyzed Skint1 expression in embryonic cTEC and mTEC subsets (Shakib et al., 2009), including immature CD80− and mature CD80+ mTEC populations shown previously to have a direct precursor-product relationship, with the latter containing Aire+ cells (Gäbler et al., 2007; Gray et al., 2007; Rossi et al., 2007). As expected, Aire expression was limited to mature CD80+ mTECs (Figure 3A), but of note this restricted pattern mirrored that of Skint1, which was undetectable in immature and mature stages of the cTEC lineage and in immature CD80− mTECs (Figure 3A).
Affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.