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.
Proceedings of the National Academy of Sciences of the United States of America
17156 - 17165
Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37232.
Cells, Cultured, Animals, Mice, Knockout, Mice, Receptors, Antigen, T-Cell, Cell Differentiation, Immune Tolerance, Natural Killer T-Cells, Nuclear Receptor Subfamily 4, Group A, Member 1, Thymocytes