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

Abstract

<jats:p>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 <jats:italic>Nr4a1</jats:italic>-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<jats:sup>tg</jats:sup>) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged <jats:italic>Vα14-Jα18</jats:italic> TCR-α chain gene into the Nur77<jats:sup>tg</jats:sup> (Nur77<jats:sup>tg</jats:sup>;Vα14<jats:sup>tg</jats: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.</jats:p>

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“…In these mice, the transcriptional activity of all three NR4As is inhibited in thymocytes, resulting in reduction of apoptosis after TCR stimulation and increasing numbers of CD4 + CD8 − thymocytes [32,62]. Next, mice were generated with constitutively overexpressed Nur77 in thymocytes showing a large decrease in thymocytes, specifically immature CD4 + CD8 + , but also CD4 + CD8 − and CD4 − CD8 + thymocyte numbers were lower [63,64]. The number of CD4 − CD8 − thymocytes showed no difference when using mice with Nur77 overexpression in multiple studies [61,63,65], whereas one study observed an increase [66] and another lower numbers [64].…”

“…Next, mice were generated with constitutively overexpressed Nur77 in thymocytes showing a large decrease in thymocytes, specifically immature CD4 + CD8 + , but also CD4 + CD8 − and CD4 − CD8 + thymocyte numbers were lower [63,64]. The number of CD4 − CD8 − thymocytes showed no difference when using mice with Nur77 overexpression in multiple studies [61,63,65], whereas one study observed an increase [66] and another lower numbers [64]. The inconsistent results obtained from these studies are most likely due to the use of different TCR transgenic backgrounds, type of T cells studied, and the stimulations applied in the accompanying in vitro experiments.…”

“…In addition, Nur77‐deficient mice show elevated CD69 and CD25 expression, suggesting increased activation of T cells [58]. Equally important, Nur77‐overexpression mice show a decrease in mature T cells in the spleen [64] and an increase in mature T cell apoptosis [66]. In addition, Nur77‐overexpression mice bear less peripheral semi‐invariant natural killer T (iNKT) cells due to high apoptotic rates [64].…”

“…Equally important, Nur77‐overexpression mice show a decrease in mature T cells in the spleen [64] and an increase in mature T cell apoptosis [66]. In addition, Nur77‐overexpression mice bear less peripheral semi‐invariant natural killer T (iNKT) cells due to high apoptotic rates [64]. Thus, impaired Nur77 expression promotes T cell activation and skews the delicate balance between proliferation and apoptosis.…”

“…Recently, it was shown that Nur77 controls development and self‐tolerance induction of iNKT cell [64]. TCR activation by agonistic self‐lipid ligands in developing thymocytes triggers iNKT cell lineage commitment, accompanied with an induction of Nur77 transcription in stage 0 iNKT cells [27].…”