Differential contributions for Bim and Nur77 in negative selection against ubiquitous and tissue-restricted self-antigens (BA2P.122)

Abstract

Abstract The thymic cortex and medulla are both sites of negative selection, where high affinity encounter with ubiquitous (UbA) and tissue-restricted (TRA) self-antigens, respectively, is thought to result in clonal deletion. Our group has shown that Bim is not required for UbA-mediated deletion but is required for TRA-mediated deletion. Nur77 is another protein implicated in thymocyte apoptosis, though its mechanism of action and regulation remain unclear. Using a physiological TCR transgenic model, HYcd4, we found that Nur77 was also dispensable for clonal deletion against UbA. Though Nur77 and its family member Nor-1 were induced during negative selection in HYcd4 Bim-/- mice, caspase-3 activation remained abrogated. Concurrent expression of a TCR transgene with a Nur77 transgene significantly inhibited Nur77-mediated thymocyte apoptosis, suggesting that TCR signalling can impair the pro-apoptotic function of Nur77. In contrast to a recent study using the OT-II Rip-mOva system, we found that Nur77 deficiency only modestly inhibited TRA-mediated clonal deletion in OT-I Rip-mOva chimeras. Furthermore, in polyclonal Bim-/- or Nur77-/- mice, we observed an increase in anergic phenotype CD4+ T cells, which may indicate an increase in self-specificities due to a block in clonal deletion. Collectively, these studies highlight potential differences in the molecular mechanisms of negative selection against UbA versus TRA, as well as of MHC class I versus MHC class II restricted thymocytes.