Lymphoid thymic inducers (green) activate RANK to turn on Aire (red) in thymic cells (blue).

A group of epithelial cells in the thymus guard against autoimmunity by presenting self-antigens to developing T cells—those T cells that take the bait are then killed. On page 1267, Rossi et al. identify the signaling pathway that creates this epithelial barrier and the cells that activate this pathway.

Self-reactive T cells are eliminated when they latch on to self-antigens presented by a small subset of medullary thymic epithelial cells (mTECs). The self-antigens are derived from tissue-restricted proteins whose genes are expressed in the specialized mTECs under the supervision of the transcription factor Aire. Humans and mice that lack Aire develop multiorgan autoimmunity, but the mechanism that turns on Aire in the mTECs was not known.

Rossi et al. now show that Aire is activated in the mTECs through signaling via the TNF family receptor RANK, which is found on mTECs. Mice that lacked RANK failed to develop Aire-expressing mTECs and consequently suffered from autoimmunity. The ligand for RANK, RANKL, was provided by a haemopoietic cell population—the lymphoid tissue inducer (LTi) cells. These cells were previously known to reside in secondary lymphoid tissue. The team now finds that the LTi cells are also present in the thymus.

Not all mTECs express Aire, but whether this exclusivity is due to selective expression of RANK is unclear. The team is now investigating how LTi cell–mediated RANK signaling gets targeted to just a small thymic population.