We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs). Promoter deletion analysis and point mutations showed that individual mutation of the GC-responsive elements does not affect GC-induced transcription and that FHRE-1 and FHRE-3 elements contribute to the effects of GCs. Furthermore, overexpression of the Forkhead transcription factor FoxO3 enhances GC-induced gilz mRNA expression. The functional significance of the interaction between FoxO3 and GC receptor was established in T lymphocytes. Indeed, we show that GCs failed to induce GILZ expression in the presence of IL-2, a cytokine known to antagonize GC effects in T cells. Using a constitutive active mutant of protein kinase B that inactivates FoxO3 or a FoxO3 mutant that cannot be inactivated by protein kinase B, we demonstrate that IL-2 inhibitory effects on GILZ expression are mediated through inhibition of FoxO3 transcriptional activity. Therefore, FoxO3 appears to be a key factor mediating GC and IL-2 antagonism for gilz regulation in T lymphocytes. This regulation of GILZ expression was placed in a meaningful context in evaluating the effects of GILZ on GC-induced apoptosis in T lymphocytes.
By revisiting CD90, a GPI-anchored glycoprotein, we show that CD90 is expressed by a subset of CD4+ and CD8+ human T cells. CD4+CD90+ cells share similarities with Th17 cells because they express the Th17-specific transcription factor RORC2 and produce IL-17A. CD4+CD90+ cells are activated memory T cells that express the gut mucosal markers CCR6, CD161, and the α4 and β7 integrins. Compared with CD90-depleted CCR6+ memory Th17 cells, CD4+CD90+ cells express higher levels of IL-22 and proinflammatory cytokines (IL-6, TNF-α and GM-CSF), but they produce lower levels of IL-21 and no IL-9. Analyses of CD8+CD90+ cells reveal that they express RORC2 and are able to produce higher levels of IL-17A, IL-22, and CCL20 compared with CD90-depleted CD8+ cells. These data show that CD90 identifies Th17 and Tc17 cells with a peculiar cytokine profile. Studies of circulating CD90+ cells in HIV patients show that CD90+ cells are decreased with an imbalance of the CD4+CD90+/regulatory T cell ratio in nontreated patients compared with treated patients and healthy donors. Overall, human CD90 identifies a subset of Th17 and Tc17 cells within CD4+ and CD8+ T cells, respectively, which are depleted during HIV infection.
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