The Nur77 family in T cell tolerance

Establishment of immune tolerance within an organism requires proper education and regulation of myriad cell types. As the organ where T cell central tolerance is enforced, the thymus purges self-reactive T cell receptor (TCR) specificities from the circulating pool. This pruning function results from cell-cell interactions between nascent T cells bearing TCR and antigen presenting cells expressing self-peptide/MHC complexes. Self-reactive thymocytes assume one of two fates: deletion via apoptotic cell death, or deviation into regulatory T cell lineages including Foxp3+ regulatory T cells (Tregs). Very little is known about the molecular pathways that drive self-reactive thymocytes towards clonal deletion or clonal deviation, and still less about the junction between them. Thymocytes accomplish deletion via activation of mitochondrial apoptosis pathways in response to TCR/MHC/self-peptide engagement, whereas deviation into thymic Tregs requires two signaling events: TCR signaling is followed by stimulation through common γ-chain cytokine receptors. What causes the strong TCR signal of deletion to diverge from its pro-apoptotic path and to become receptive to this second signal is unknown. One molecule implicated in central tolerance is the nuclear receptor Nur77. Nur77 and the closely-related molecules Nor-1 and Nurr1 have been associated with both apoptosis and survival in different conditions and cell types. In the thymus, Nur77 mRNA expression is induced in activated CD4+CD8+ thymocytes and correlates with apoptosis. We observed direct evidence for Nur77 participation in both clonal deletion and clonal deviation. Using BDC2.5 TCR transgenic fetal thymic organ culture and OT-II/RIP-mOVA TCR/antigen double transgenic mice, we observed subtle but consistent defects in antigen-specific thymocyte deletion in Nur77KO. We also hypothesize that Nur77 expression impedes Treg differentiation; Nur77KO resulted in a doubling of Foxp3+ CD4SP thymic Tregs as well as their CD25+ Foxp3- CD4SP precursors. Transcriptional analyses performed on stimulated thymocytes from Nur77 KO mice revealed a set of Nur77-regulated genes including Eno3 and Bim that may commit cells to clonal deletion at the expense of Treg differentiation. Together, these results mark Nur77 as the first molecule to participate in both deletion and Treg differentiation, with broad implications for T cell tolerance.