Rank Signaling Links the Development of Invariant γδ T Cell Progenitors and Aire ⁺ Medullary Epithelium

Summary

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. Here we showed that emergence of the first cohorts of Aire ⁺ mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl ⁺ lymphoid tissue inducer cells and invariant Vγ5 ⁺ dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. 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.

Abstract

Graphical Abstract

Highlights

► Invariant Vγ5 ⁺ thymocytes regulate formation of Aire ⁺ medullary thymic epithelium ► Generation of an invariant Vγ5 ⁺ T cell population requires thymus medulla development ► Skint-1-mediated Vγ5 ⁺ thymocyte development is Aire independent ► Dependency on Tnfrsf11a links γδ T cell and medullary epithelium development