Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation

Immune protection and lasting memory are accomplished through the generation of phenotypically and functionally distinct CD8 T cell subsets. Understanding how these effector and memory T cells are formed is the first step in eventually manipulating the immune system for therapeutic benefit. In this review, we will summarize the current understanding of CD8 T cell differentiation upon acute infection, with a focus on the transcriptional and epigenetic regulation of cell fate decision and memory formation. Moreover, we will highlight the importance of high throughput sequencing approaches and single cell technologies in providing insight into genome-wide investigations and the heterogeneity of individual CD8 T cells

Buddhist monasteries facilitated landscape conservation on the Qinghai-Tibetan Plateau

Context: The Sanjiangyuan region of the Qinghai-Tibetan Plateau—also known as the “Three Rivers’ Headwaters”—is the origin of the Yellow, Yangtze, and Mekong Rivers and therefore the key water source for hundreds of millions of downstream residents. Protecting this region’s ecosystems is a key priority for sustainable development in China and Asia. An important social dimension of Sanjiangyuan is the long-established and widespread presence of Tibetan Buddhism, particularly as manifested in the large number of monasteries throughout the region. However, the influence of cultural factors on environmental change remains largely understudied here. / Objective: We focus on two types of spatial associations—point-point and point-area features—to quantitatively investigate the effects of Buddhist monasteries on land use/cover change (LUCC) in surrounding landscapes. / Methods: We conduct a spatially-explicit analysis of Sanjiangyuan for two periods, 1990–2000 and 2010–2015, to identify and quantify the influence of the presence and spatial distributions of Buddhist monasteries on LUCC compared to village communities that lack monasteries. / Results: We found that the presence of monasteries is highly correlated with the preservation of natural ecosystems, specifically of grasslands and forests. Within monastery buffer zones with radii between 1 and 10 km, 7.13–9.30% more grassland area and 7.14–7.47% more forest area remained around monasteries compared to villages. This contrast decreased with increasing distance to the monastery/village. Overall, built-up areas were also much smaller around monasteries than around villages, while unused land was more commonly transformed to forests and grasslands around monasteries. / Conclusions: These findings strongly support the idea that Buddhist culture, as manifested through its physical institutions and communities, are instrumental in achieving desired landscape conservation outcomes

Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

Comprehensive Evaluation of Self-Healing Polyampholyte Gel Particles for the Severe Leakoff Control of Drilling Fluids

Lost circulation has been a serious problem to be solved in many drilling practices during oil, gas and geothermal well drillings. Many materials have been developed and evaluated for the purpose. However, their performance to plug severe leakoff is very limited. Herein, an injectable self-healing hydrogel based on polyampholyte with sulfonated and quaternary ammonium functionalities (P(MPTC-co-NaSS)) was developed and comprehensively evaluated to prevent the severe loss of fluids to formation. By incorporating cation-π (π is for aromatic residues) interaction, the hydrogel shown self-healing property and robustness in severe environment (temperature, salt) by comparison with other hydrogels merely consisting of cation-anion and H-bonding interactions. Aromatic residues enhanced thermal stability above 310 °C. The plugging measurement shown that an addition of 2 wt% dried gel particles can plug high-permeability formation and endure a high pressure of 6 MPa, produce much lower circulation loss and result in a dramatically increased loss volume reduction rate (63.5%) compared with a commercial polymer gel product and an inert material (9.4%) after a self-healing process. Markedly, P(MPTC-co-NaSS) can be used in a wide range of formation temperature (as high as 150 °C) and salt concentrations (NaCl, CaCl2, as high as 15 wt %). In addition to suitable particle size and mechanically robustness, it was also attributed to the soft, swelling, deformable, toughness and self-healable features of P(MPTC-co-NaSS) gel particles as well as the strong adhesion to negatively charged formations in water, even under high thermal and saline condition. These characteristics also contributed to a long-term plugging performance, beneficial to avoid repeated lost circulation in drilling operation. Besides, this self-healing polyampholyte gel particles dispersed well in saline fluid and maintained stable rheological properties after hot rolling, which was favorable to drilling fluid circulation. This study shown the application potential of self-healing materials as plugging material candidate in petroleum drilling industry

IL-1 receptor–associated kinase M is a central regulator of osteoclast differentiation and activation

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis. Interleukin (IL)-1 receptor (IL-1R)–associated kinase M (IRAK-M) is only expressed in cells of the myeloid lineage and it inhibits signaling downstream of IL-1R and Toll-like receptors (TLRs). However, it lacks a functional catalytic site and, thus, cannot function as a kinase. IRAK-M associates with, and prevents the dissociation of, IRAK–IRAK-4–TNF receptor–associated factor 6 from the TLR signaling complex, with resultant disruption of downstream signaling. Thus, IRAK-M acts as a dominant negative IRAK. We show here that mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Ligation of IL-1R or TLRs results in hyperactivation of NF-κB and mitogen-activated protein kinase signaling pathways, which are essential for osteoclast differentiation. Thus, IRAK-M is a key regulator of the bone loss that is due to osteoclastic resorption of bone

CXCR5+PD-1+ follicular helper CD8 T cells control B cell tolerance

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4+ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5+PD1+ Tfh subset of CD8+ T cells whose development and function are negatively modulated by Stat5. These CD8+ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8+ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8+ Tfh cells share similar gene signatures with CD4+ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance

Anti-platelet properties of Pim kinase inhibition is mediated through disruption of thromboxane A2 receptor signalling

Pim kinases are upregulated in several forms of cancer, contributing to cell survival and tumour development, but their role in platelet function and thrombotic disease has not been explored. We report for the first time that Pim-1 kinase is expressed in human and mouse platelets. Genetic deletion or pharmacological inhibition of Pim kinase results in reduced thrombus formation but is not associated with impaired haemostasis. Attenuation of thrombus formation was found to be due to inhibition of the thromboxane A2 receptor as effects on platelet function was non-additive to inhibition caused by the cyclooxygenase inhibitor indomethacin or thromboxane A2 receptor antagonist GR32191. Treatment with Pim kinase inhibitors caused reduced surface expression of the thromboxane A2 receptor and resulted in reduced responses to thromboxane A2 receptor agonists, indicating a role for Pim kinase in the regulation of thromboxane A2 receptor function. Our research identifies a novel, Pim kinase dependent regulatory mechanism for the thromboxane A2 receptor and represents a new targeting strategy that is independent of COX- 1 inhibition or direct antagonism of the thromboxane A2 receptor that whilst attenuating thrombosis does not increase bleeding

A Common SMAD7 Variant Is Associated with Risk of Colorectal Cancer: Evidence from a Case-Control Study and a Meta-Analysis

<div><h3>Background</h3><p>A common genetic variant, rs4939827, located in <em>SMAD7</em>, was identified by two recent genome-wide association (GWA) studies to be strongly associated with the risk of colorectal cancer (CRC). However, the following replication studies yielded conflicting results.</p> <h3>Method and Findings</h3><p>We conducted a case-control study of 641 cases and 1037 controls in a Chinese population and then performed a meta-analysis, integrating our and published data of 34313 cases and 33251 controls, to clarify the relationship between rs4939827 and CRC risk. In our case-control study, the dominant model was significant associated with increased CRC risk [Odds Ratio (OR) = 1.46; 95% confidence interval (95% CI), 1.19–1.80]. The following meta-analysis further confirmed this significant association for all genetic models but with significant between-study heterogeneity (all <em>P</em> for heterogeneity <0.1). By stratified analysis, we revealed that ethnicity, sample size, and tumor sites might constitute the source of heterogeneity. The cumulative analysis suggested that evident tendency to significant association was seen with adding study samples over time; whilst, sensitive analysis showed results before and after removal of each study were similar, indicating the highly stability of the current results.</p> <h3>Conclusion</h3><p>Results from our case-control study and the meta-analysis collectively confirmed the significant association of the variant rs4939827 with increased risk of colorectal cancer. Nevertheless, fine-mapping of the susceptibility loci defined by rs4939287 should be imposed to reveal causal variant.</p> </div