Highlights • CXCR5+ CD4+ T cells represent a circulating memory compartment of Tfh lineage cells. • Blood memory Tfh cells are composed of phenotypically and functionally distinct subsets. • A ...proposed 3D approach defines nine blood memory Tfh subsets.
T follicular helper (Tfh) cells represent a Th subset engaged in the help of B-cell responses in germinal centers (GCs). Tfh cells abundantly express the transcription repressor B-cell lymphoma 6 ...(Bcl6), a factor that is necessary and sufficient for their development in vivo. Whether Tfh or Tfh-committed cells are involved in the help of B cells outside GCs remains unclear, particularly in humans. In this study, we identified a previously undefined BCL6-expressing CD4+ T-cell subset in human tonsils. This subset expressed IL-7 receptor and chemokine receptor 5 (CXCR5) and inducible costimulator (ICOS) at low levels (CXCR5loICOSlo), and it was found exclusively outside GCs. CXCR5loICOSlo CD4+ T cells secreted larger amounts of IL-21 and IL-10 than CXCR5hiICOShi GC-Tfh cells upon activation, and they induced proliferation and differentiation of naïve B cells into Ig-producing cells more efficiently than GC-Tfh cells. However, this subset lacked the capacity to help GC-B cells because of the induction of apoptosis of GC-B cells through the FAS/FAS–ligand interaction. CXCR5loICOSlo CD4+ T cells expressed equivalent amounts of BCL6 transcript with CXCR5hiICOShi GC-Tfh cells, but they expressed less Bcl6 protein. Collectively, our study indicates that CXCR5loICOSlo CD4+ T cells in human tonsils represent Tfh lineage-committed cells that provide help to naïve and memory B cells outside GCs.
Highlights • Development of Th1, Th2, Th9, and Th22 is largely similar between mice and humans. • TGF-β and STAT3 signals promote Th17 differentiation in both species. • Some differences exist in the ...development of induced Tregs, Th17, and Tfh cells. • Human Th differentiation is largely regulated by IL-12, IL-23, and TGF-β.
IL-12 is important for the differentiation of T follicular helper (Tfh) cells, as well as Th1 cells in humans. Still, how IL-12 signals regulate Tfh versus Th1 cell differentiation remains poorly ...characterized. Here we aimed to determine the molecular mechanisms that regulate the differentiation and the function of IL-12-stimulated human naive CD4+ T cells. We found that T-bet promoted the expression of CXCR5 in human CD4+ T cells. We provide evidence that T-bet does not strongly inhibit the Tfh cell differentiation program per se but diminishes the functions to provide help to B cells. This study also suggests that IRF4 plays an important role in driving the early differentiation of IL-12-stimulated CD4+ T cells toward Tfh and away from Th1 by inhibiting the expression of Eomesodermin. Thus, the fate of IL-12-stimulated CD4+ T cells is determined through interplay of multiple transcription factors at early stages.
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•T-bet promotes CXCR5 expression by human CD4+ T cells•T-bet does not strongly affect Bcl-6 or Blimp-1 expression in human CD4+ T cells•T-bet regulates the helper functions of IL-12-stimulated human CD4+ T cells•IRF4 seems to tip the balance of Tfh and Th1 differentiation toward Tfh
Schmitt et al. suggest that Th1 transcription factor T-bet does not strongly inhibit the Tfh cell differentiation program per se but diminishes the helper functions of developing Tfh cells. IRF4 seems important in tipping the balance of Tfh and Th1 differentiation toward Tfh at early stages.
Immunity results from a complex interplay between the antigen‐non‐specific innate immune system and the antigen‐specific adaptive immune system. The cells and molecules of the innate system employ ...non‐clonal recognition receptors including lectins, Toll‐like receptors, NOD‐like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines.
Purpose
The patency of arterial catheters is essential for reliable invasive blood pressure monitoring. We sought to determine whether radial catheter failures were associated with intravascular ...thrombosis in critically ill adult patients.
Methods
This unmatched case-control study was conducted within a prospective cohort of patients admitted to an intensive care unit. The arterial catheter failure was the main outcome, which identified cases. Controls were patients with patent catheter until removal or 28 days of follow-up. The prevalence of intravascular thrombosis in cases and controls was determined by ultrasonography of the cannulated radial artery. Assessors were blinded to clinical findings. Failing catheters were removed and examined microscopically.
Results
Catheter failures occurred in 25.5% of 200 patients during 584 catheter-days (incidence rate, 87/1000 catheter-days). The median patency duration was 13.1 days. An intravascular thrombosis located in front of the catheter tip was diagnosed in 42 of 50 cases (84.0%) and 24 of 139 controls (17.3%). In multivariable logistic regression analysis, the probability of catheter failure was higher in patients with intravascular thrombosis odds ratio (OR), 36.52; 95% confidence interval (CI), 12.86–103.74 and females (OR, 3.45; 95% CI 1.32–9.05), increased proportionally to arterial blood sampling frequency (OR, 1.20; 95% CI 1.04–1.38), and decreased in thrombocytopenia (OR, 0.28; 95% CI 0.10–0.78). After removal, 15.7% of failing catheters had some luminal fibrin deposits, but none were occluded.
Conclusions
Most failing radial arterial catheters had no luminal obstruction, but were associated with an intravascular thrombosis. Among predictive factors, arterial blood sampling frequency is the most susceptible to intervention.
Autophagy is a catabolic process that enables cells to degrade obsolete content and refuel energy depots. In colorectal cancer (CRC) autophagy has been shown to promote tumorigenesis through energy ...delivery in the condition of uncontrolled proliferation. With this study, we aimed at evaluating whether autophagy sustains CRC cell viability and if it impacts therapy resistance. Initially, a colorectal cancer tissue micro array, containing mucosa (
= 10), adenoma (
= 18) and adenocarcinoma (
= 49) spots, was stained for expression of essential autophagy proteins LC3b, Atg7, p62 and Beclin-1. Subsequently, central autophagy proteins were downregulated in CRC cells using siRNA technology. Viability assays, flow cytometry and immunoblotting were performed and three-dimensional cell culture was utilized to study autophagy in a tissue mimicking environment. In our study we found an upregulation of Atg7 in CRC. Furthermore, we identified Atg7 as crucial factor within the autophagy network for CRC cell viability. Its disruption induced cell death via triggering apoptosis and in combination with conventional chemotherapy it exerted synergistic effects in inducing CRC cell death. Cell death was strictly dependent on nuclear LC3b, since simultaneous knockdown of Atg7 and LC3b completely restored viability. This study unravels a novel cell death preventing function of Atg7 in interaction with LC3b, thereby unmasking a promising therapeutic target in CRC.
Avoidance of therapy-induced apoptosis is a hallmark of acquired resistance towards radiotherapy. Thus, breaking resistance still challenges modern cancer therapy. The Bcl-2 protein family is known ...for its regulatory role in apoptosis signaling, making Bcl-2, Mcl-1 and Bcl-xL promising targets. This study evaluates the effects of highly specific inhibitors for Bcl-xL (WEHI-539), Bcl-2 (ABT-199) and Mcl-1 (S63845) as radiosensitizers. Covering a broad spectrum of solid tumors, Non-Small-Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC) and synovial sarcoma cell lines were exposed to fractionated radiation as standard therapy with or without Bcl-2 protein inhibition. Protein expression was detected by Western blot and cell death was assessed by flow cytometry measuring apoptosis. In contrast to NSCLC, a high level of Bcl-xL and its upregulation during radiotherapy indicated radioresistance in HNSCC and synovial sarcoma. Radioresistant cell lines across all entities benefited synergistically from combined therapy with Bcl-xL inhibition and fractionated radiation. In NSCLC cell lines, Mcl-1 inhibition significantly augmented radiotherapy independent of the expression level. Our data suggest that among antiapoptotic Bcl-2 proteins, targeting Bcl-xL may break resistance to radiation in HNSCC, synovial sarcoma and NSCLC in vitro. In NSCLC, Mcl-1 might be a promising target that needs further investigation.
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