Nur77 controls tolerance induction, terminal differentiation, and effector functions in semi-invariant natural killer T cells

Significance

Semi-invariant natural killer T (iNKT) cells are innate-like lymphocytes that control a variety of immune functions. iNKT cell functions are mediated by high-affinity interactions with self-agonists displayed by the lipid-presenting CD1d molecule. How iNKT cells attain tolerance to high-affinity interactions with self remains unknown. This understanding is of immunologic import, as an unbridled iNKT cell-mediated response can cause inflammatory diseases. We discovered that Nur77—a transcription factor expressed at high levels in iNKT cells—induced caspase-3–mediated apoptosis and markers of T cell exhaustion such as PD-1 in iNKT cell precursors, which led to hyporesponsiveness to a high-affinity lipid agonist. Thus, Nur77 plays a central role in self-tolerance induction of iNKT cells.

Abstract

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 Nr4a1-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^tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77^tg(Nur77^tg;Vα14^tg) 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.