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¹ Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, B15 2TT Birmingham, UK
² Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria
³ Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, 3050 Victoria, Australia

CORRESPONDENCE Graham Anderson: g.anderson{at}bham.ac.uk

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4⁺3^– inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4⁺3^– cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire⁺ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80^–Aire^– mTEC progenitors into CD80⁺Aire⁺ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire⁺ mTECs and highlight a previously unrecognized role for CD4⁺3^–RANKL⁺ inducer cells in intrathymic self-tolerance.

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