Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption.

Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as APCs. Cross-presentation of Ags by osteoclasts leads to expression of CD25 and Foxp3, markers of regulatory T cells in the CD8 T cells. Octeoclast-induced Foxp3(+) CD25(+) regulatory CD8 T cells (OC-iTcREG) suppress priming of CD4 and CD8 T cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. In this study, we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet, and Eomes production by TcREG Furthermore, we show, using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoters. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of TNFR-associated factor 6 in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ(-/-) T cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose receptor activator of NF-κB ligand. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish an important role for IFN-γ in TcREG-mediated protection from bone loss.

Real-World Impact of Retrievable Stents for Acute Ischemic Stroke on Disability Utilizing the National Inpatient Sample.

PURPOSE: We assess the impact of retrievable stent (RS) compared to first-generation devices on in-hospital mortality and disability in patients with acute ischemic stroke (AIS). METHODS: Using the National Inpatient Sample, data were obtained for patients with a primary diagnosis of AIS who underwent mechanical thrombectomy (MT) and were admitted to US hospitals between 2010 and 2014. Two time periods were compared: 2010-2012 (pre-RS Food and Drug Administration [FDA] approval) and 2013-2014 (post-RS FDA approval). Disability level was used to classify outcomes as minimal disability, moderate to severe disability, or in-hospital mortality. Weighted, multivariable logistic regression was used to assess the association between MT device type and disability. RESULTS: A total of 2,443,713 weighted patients admitted with AIS were identified; 148,923 (4.9%) of these received intravenous tissue plasminogen activator; and 23,719 (0.8%) underwent MT. In multivariable logistic regression analysis, the odds of in-hospital mortality decreased (OR 0.69, 95% CI 0.59-0.82) in the post-RS time-period compared with pre-RS time. The odds of moderate-to-severe disability decreased (OR 0.88, 95% CI 0.73-1.06) compared with minimal disability. In-hospital mortality rates decreased successively over the 4 years in the MT-treated patients (p < 0.001). CONCLUSIONS: The FDA approval of RS technology after 2012 was associated with decreased in-hospital mortality when compared with the 3-year interval prior. These findings provide an indication that the RCT data on the efficacy of RS technology are translating into improved real-world outcomes.