CD4(+) regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 have a pivotal role in maintaining immunological tolerance. Here we show that mice with T cell-specific deletion of both the Foxo1 and Foxo3 transcription factors (collectively called 'Foxo proteins' here) developed a fatal multifocal inflammatory disorder due in part to T(reg) cell defects. Foxo proteins functioned in a T(reg) cell-intrinsic manner to regulate thymic and transforming growth factor-beta (TGF-beta)-induced Foxp3 expression, in line with the ability of Foxo proteins to bind to Foxp3 locus and control Foxp3 promoter activity. Transcriptome analyses showed that Foxo proteins regulated the expression of additional T(reg) cell-associated genes and were essential for inhibiting the acquisition of effector T cell characteristics by T(reg) cells. Thus, Foxo proteins have crucial roles in specifying the T(reg) cell lineage.
Summary Members of the Forkhead box O (Foxo) family of transcription factors are key regulators of cellular responses, but their function in the immune system remains incompletely understood. Here we show that T cell-specific deletion of Foxo1 gene in mice led to spontaneous T cell activation, effector T cell differentiation, autoantibody production, and the induction of inflammatory bowel disease in a transfer model. In addition, Foxo1 was critical for the maintenance of naïve T cells in the peripheral lymphoid organs. Transcriptome analyses of T cells identified Foxo1-regulated genes encoding, among others, cell surface molecules, signaling proteins, and nuclear factors that control gene expression. Functional studies validated interleukin 7 receptor-α as a Foxo1 target gene essential for Foxo1 maintenance of naïve T cells. These findings reveal crucial functions of Foxo1-dependent transcription in control of T cell homeostasis and tolerance.
Summary Thymus-derived naturally occurring regulatory T cells (nTregs) are necessary for immunological self-tolerance. nTreg development is instructed by the T cell receptor, and can be induced by agonist antigens that trigger T cell negative selection. How T cell deletion is regulated so that nTregs are generated is unclear. Here we showed that transforming growth factor-β (TGF-β) signaling protected nTregs and antigen-stimulated conventional T cells from apoptosis. Enhanced apoptosis of TGF-β receptor-deficient nTregs was associated with high expression of pro-apoptotic proteins Bim, Bax, and Bak, and low expression of the anti-apoptotic protein Bcl-2. Ablation of Bim in mice corrected the Treg development and homeostasis defects. Our results suggest that nTreg commitment is independent of TGF-β signaling. Instead, TGF-β promotes nTreg survival by antagonizing T cell negative selection. These findings reveal a critical function for TGF-β in control of autoreactive T cell fates with important implications for understanding T cell self-tolerance mechanisms.
Background Neonatal hypoglycemia has been associated with various forms of neurological impairment including developmental delay, seizures, visual processing problems, and cognitive difficulties [1]. Consensus guidelines have been created to expedite the identification and resolution of hypoglycemic episodes. Interventions, such oral dextrose gel, have been shown to quickly and effectively reverse episodes of severe hypoglycemia [2]. However, more research needs to be conducted to quantify potential effects of oral glucose gel pathways on prevention of hypoglycemia in the neonatal period. Objective We evaluated the effects of introducing a clinical pathway for improving hypoglycemia with oral dextrose gel. We hypothesized a decrease in the length of stay of neonates with hypoglycemia after the introduction of the clinical pathway. Design/Methods We conducted a retrospective chart review evaluating neonates born ≥ 35 weeks gestational age, who exhibited asymptomatic hypoglycemia within 48 hours of life (HOL) while receiving exclusive oral feeds. The primary outcome was overall length of hospital stay. We extracted data from charts of children born prior and after the implementation of this oral dextrose gel pathway in both the well-baby nursery and Neonatal Intensive Care Unit (NICU) of a single medical center over a one-year period. Results 385 total neonates who fit the aforementioned criteria were included, with 175 neonates representing the historical control group and 210 neonates in the intervention group receiving oral dextrose gel. Analysis demonstrated no significant difference in the overall length of stay, as well as the total episodes of hypoglycemia and number of days the neonate received intravenous fluid therapy with dextrose. Conclusion(s) Our study demonstrates that the introduction of oral dextrose gel pathway did not have a significant effecton the overall length of hospital stay, as well as the total episodes of hypoglycemia and number of days the neonate received intravenous fluid therapy with dextrose at our institution. Further research is needed to evaluate whether response to oral dextrose gel can be used as a predictor of severe hypoglycemia in the neonatal period. Presentation: No date and time listed
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