Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.
Roberts NA., White AJ., Jenkinson WE., Turchinovich G., Nakamura K., Withers DR., McConnell FM., Desanti GE., Benezech C., Parnell SM., Cunningham AF., Paolino M., Penninger JM., Simon AK., Nitta T., Ohigashi I., Takahama Y., Caamano JH., Hayday AC., Lane PJ., Jenkinson EJ., Anderson G.
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.