No abstract

SummaryExpansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation of the complement receptor CD46, and specifically its intracellular domain CYT-1, was required for induction of the amino acid (AA) transporter LAT1 and enhanced expression of the glucose transporter GLUT1. Furthermore, CD46 activation simultaneously drove expression of LAMTOR5, which mediated assembly of the AA-sensing Ragulator-Rag-mTORC1 complex and increased glycolysis and oxidative phosphorylation (OXPHOS), required for cytokine production. T cells from CD46-deficient patients, characterized by defective Th1 cell induction, failed to upregulate the molecular components of this metabolic program as well as glycolysis and OXPHOS, but IFN-γ production could be reinstated by retrovirus-mediated CD46-CYT-1 expression. These data establish a critical link between the complement system and immunometabolic adaptations driving human CD4+ T cell effector function.

This study provides strong and consistent support for the linkage to essential hypertension of regions within or close to the angiotensinogen gene. Precisely how mutations in this region may result in hypertension remains to be determined.

No abstract

A sthma is a chronic inflammatory disease which is accompanied by extensive changes in normal airway tissue architecture, termed remodeling (1, 2). Airway remodeling in asthma comprises epithelial dysfunction, hypertrophy of the mucus glands, subepithelial vascularization, and changes in extracellular matrix composition (2). In addition, airway smooth muscle (ASM) from people suffering with asthma exhibits enhanced proliferative (3) and migratory responses (4, 5), as well as increased secretion of a myriad of pro-inflammatory cytokines/ chemokines and growth factors (6). The mechanisms that underly the exaggerated function of ASM in asthma are unknown.Smooth muscle responses to diverse stimuli are controlled by changes in the concentration of free cytosolic Ca 2ϩ ([Ca 2ϩ ] i ). Elevation of [Ca 2ϩ ] i results from increased Ca 2ϩ influx across the plasma membrane following activation of Ca 2ϩ -permeable ion channels and the Na ϩ -Ca 2ϩ -exchanger (NCX, 3Na ϩ :1Ca 2ϩ ), and by release of stored Ca 2ϩ from the sarcoplasmic reticulum (SR), in turn triggered by inositol 1,4,5-triphosphate (IP 3 ) or ryanodine receptor (RyR) channels (7). Termination of the cytosolic Ca 2ϩ signal occurs by extracellular removal of cytosolic Ca 2ϩ by the NCX and by its rapid sequestration into SR stores by the sarco/endoplasmic reticulum Ca 2ϩ (SERCA) pump (7). Impaired replenishment of SR stores arising from reduced activity of the SERCA pump could impact on a wide range of Ca 2ϩ -dependent smooth muscle functions (8) and abnormal Ca 2ϩ handling by ASM has previously been proposed to be an important determinant of the airway hyperresponsiveness that is characteristically present in asthma (9, 10).There are 3 tissue-specific members of the mammalian SERCA family, SERCA1, SERCA2 and SERCA3, each encoded by a separate gene (ATP2A1, ATP2A2, and ATP2A3) (11), with SERCA2 being the most highly expressed in smooth muscle (12, 13). The function of the different isoforms of SERCA2 is similar (14). We have investigated if the secretory and hyperproliferative phenotype of ASM in asthma is associated with impaired SERCA isoform expression. Results SERCA2Expression. SERCA2 mRNA expression was reduced in ASM cells cultured from patients with moderate, but not mild asthma compared with cells derived from healthy subjects (P ϭ 0.04, Fig. 1A). Western immunoblot showed a single band for SERCA2 at the expected size (Ϸ110 kDa) in ASM lysates (Fig. 1). SERCA2 protein expression was correspondingly reduced in ASM cells from patients with moderate asthma (P ϭ 0.015, Fig. 1B). In contrast, IP 3 R1 mRNA and protein expression did not differ between asthmatics and controls ( Fig. 1 A and B), suggesting the change in SERCA2 was not the result of a reduction in total SR. Transcripts for SERCA1, and SERCA3 were not detected in ASM. Further experiments using SERCA2A, SERCA2B, and SERCA2C specific primers demonstrated that predominant isoform in ASM is SERCA2B with the other isoforms expressed at very low levels around the limit of detection. The pattern of ...

Highlights d Diapedesis induces C3 expression as a feature of immune cells in tissue d C3 transcription is LFA-1 dependent and integral to normal immune cell activity d Defective C3 expression underlies human primary immune deficiency disease LAD-1 d The integrin network is a key driver of complosome activity and cell function

Using a functional screen in Xenopus embryos, we identified a novel function for the HMG box protein XSox17 beta. Ectopic expression of XSox17 beta ventralizes embryos by inhibiting the Wnt pathway downstream of beta-catenin but upstream of the Wnt-responsive gene Siamois. XSox17 beta also represses transactivation of a TCF/LEF-dependent reporter construct by Wnt and beta-catenin. In animal cap experiments, it both activates transcription of endodermal genes and represses beta-catenin-stimulated expression of dorsal genes. The inhibition activity of XSox17 beta maps to a region C-terminal to the HMG box; this region of XSox17 beta physically interacts with the Armadillo repeats of beta-catenin. Two additional Sox proteins, XSox17 alpha and XSox3, likewise bind to beta-catenin and inhibit its TCF-mediated signaling activity. These results reveal an unexpected mechanism by which Sox proteins can modulate Wnt signaling pathways.

The molecular mechanisms governing orderly shutdown and retraction of CD4 + T helper (Th)1 responses remain poorly understood. Here, we show that complement triggers contraction of Th1 responses by inducing intrinsic expression of the vitamin D (VitD) receptor (VDR) and the VitD-activating enzyme CYP27B1, permitting T cells to both activate and respond to VitD. VitD then initiated transition from pro-inflammatory IFN-γ + Th1 cells to suppressive IL-10 + cells. This process was primed by dynamic changes in the epigenetic landscape of CD4 + T cells, generating super-enhancers and recruiting several transcription factors, notably c-JUN, STAT3 and BACH2, which together with VDR shaped the transcriptional response to VitD. Accordingly, VitD did not induce IL-10 in cells with dysfunctional BACH2 or STAT3. Bronchoalveolar lavage fluid CD4 + T cells of COVID-19 patients were Th1-skewed and showed de-repression of genes down-regulated by VitD, either from lack of substrate (VitD deficiency) and/or abnormal regulation of this system.