Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells.
Kumar A., Hill TM., Gordy LE., Suryadevara N., Wu L., Flyak AI., Bezbradica JS., Van Kaer L., Joyce S.
Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of <i>Nr4a1</i>-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77<sup>tg</sup>) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged <i>Vα14-Jα18</i> TCR-α chain gene into the Nur77<sup>tg</sup> (Nur77<sup>tg</sup>;Vα14<sup>tg</sup>) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.