Research on IBDs has identified disrupted immune responses in the gastrointestinal mucosa and putative disruptions in the gut microbiome as causative agents. This work has led to better therapeutic ...control of IBDs with the use of various antiinflammatory agents.
Tissue-resident memory T cells (T
cells) provide protective immunity, but the contributions of specific tissue environments to T
cell differentiation and homeostasis are not well understood. In the ...present study, the diversity of gene expression and genome accessibility by mouse CD8
T
cells from distinct organs that responded to viral infection revealed both shared and tissue-specific transcriptional and epigenetic signatures. T
cells in the intestine and salivary glands expressed transforming growth factor (TGF)-β-induced genes and were maintained by ongoing TGF-β signaling, whereas those in the fat, kidney and liver were not. Constructing transcriptional-regulatory networks identified the transcriptional repressor Hic1 as a critical regulator of T
cell differentiation in the small intestine and showed that Hic1 overexpression enhanced T
cell differentiation and protection from infection. Provision of a framework for understanding how CD8
T
cells adapt to distinct tissue environments, and identification of tissue-specific transcriptional regulators mediating these adaptations, inform strategies to boost protective memory responses at sites most vulnerable to infection.
Immunological memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Here we highlight advances in the understanding of the diverse T lymphocyte subsets ...that provide acute and long-term protection from infection. These include new insights into the transcription factors, and the upstream 'pioneering' factors that regulate their accessibility to key sites of gene regulation, as well as metabolic regulators that contribute to the differentiation of effector and memory subsets; ontogeny and defining characteristics of tissue-resident memory lymphocytes; and origins of the remarkable heterogeneity exhibited by activated T cells. Collectively, these findings underscore progress in delineating the underlying pathways that control diversification in T cell responses but also reveal gaps in the knowledge, as well as the challenges that arise in the application of this knowledge to rationally elicit desired T cell responses through vaccination and immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Extending the light absorption range of wide‐bandgap photocatalysts into the visible light region is significant in terms of fully harvesting and converting solar light. The desirable band‐to‐band ...redshift of the absorption edge of semiconducting binary metal oxides such as prototypical photocatalyst TiO2 by doping is long targeted but remains a challenge, up to date. Here, by taking the advantage of abundant 1D diffusion channels with rhombus‐like cross‐sections along the c‐axis in the crystal structure of titanium oxalate hydrate to promote the entrance of nitrogen dopant species into the bulk and subsequent thermal topotactic transition in an atmosphere of gaseous ammonia, homogeneous doping of substitutional carbon/nitrogen for oxygen in the TiO2 decahedral plates with a dominant anatase phase is obtained for the first time. The resultant TiO2−x(CN)y with an unusual band‐to‐band visible light absorption spectrum can induce photocatalytic water oxidation to release oxygen under visible light irradiation. This study provides not only a promising visible light–responsive TiO2 photocatalyst, but also an important strategy for developing other solar‐driven photocatalysts.
Homogeneous doping of substitutional carbon/nitrogen to oxygen in TiO2, which is realized by the thermal topotactic transition of titanium oxalate hydrate with abundant 1D spaces in the ammonia atmosphere, leads to a desirable band‐to‐band visible light absorption spectrum. The resultant TiO2−x(CN)y sample as a stable photocatalyst has the ability of inducing water oxidation to release oxygen under visible light irradiation.
Tissue-resident memory CD8+ T cells (Trm) provide host protection through continuous surveillance of non-lymphoid tissues. Using single-cell RNA-sequencing (scRNA-seq) and genetic reporter mice, we ...identified discrete lineages of intestinal antigen-specific CD8+ T cells, including a Blimp1hiId3lo tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1loId3hi tissue-resident memory population that subsequently accumulated at later infection time points. These Trm populations exhibited distinct cytokine production, secondary memory potential, and transcriptional programs including differential roles for transcriptional regulators Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm. Extending our analysis to malignant tissue, we also identified discrete populations of effector-like and memory-like CD8+ T cell populations with tissue-resident gene-expression signatures that shared features of terminally exhausted and progenitor-exhausted T cells, respectively. Our findings provide insight into the development and functional heterogeneity of Trm cells, which has implications for enhancing vaccination and immunotherapy approaches.
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•Blimp1 and Id3 expression identify distinct tissue-resident T cell subsets•Id3hi siIEL CD8+ T cells exhibit heightened multifunctionality and memory potential•Id2 and Id3 are required for homeostasis of tissue-resident memory cells•Id3hi cells in tumors have features of tissue-residency and progenitor exhausted cells
Tissue-resident memory CD8+ T cells (Trm) provide long-lasting immunity in non-lymphoid tissues. Milner et al. use single-cell RNA sequencing to reveal Trm cell heterogeneity in response to infection and identify effector-like Id3loBlimp1hi and memory-like Id3hiBlimp1lo tissue-resident populations with differential effector function, memory potential, and transcriptional programming. Analogous populations of CD8+ T cells with tissue-residency features were also identified in tumors.
Tissue-resident memory T (T
) cells persist indefinitely in epithelial barrier tissues and protect the host against pathogens. However, the biological pathways that enable the long-term survival of T
...cells are obscure. Here we show that mouse CD8
T
cells generated by viral infection of the skin differentially express high levels of several molecules that mediate lipid uptake and intracellular transport, including fatty-acid-binding proteins 4 and 5 (FABP4 and FABP5). We further show that T-cell-specific deficiency of Fabp4 and Fabp5 (Fabp4/Fabp5) impairs exogenous free fatty acid (FFA) uptake by CD8
T
cells and greatly reduces their long-term survival in vivo, while having no effect on the survival of central memory T (T
) cells in lymph nodes. In vitro, CD8
T
cells, but not CD8
T
cells, demonstrated increased mitochondrial oxidative metabolism in the presence of exogenous FFAs; this increase was not seen in Fabp4/Fabp5 double-knockout CD8
T
cells. The persistence of CD8
T
cells in the skin was strongly diminished by inhibition of mitochondrial FFA β-oxidation in vivo. Moreover, skin CD8
T
cells that lacked Fabp4/Fabp5 were less effective at protecting mice from cutaneous viral infection, and lung Fabp4/Fabp5 double-knockout CD8
T
cells generated by skin vaccinia virus (VACV) infection were less effective at protecting mice from a lethal pulmonary challenge with VACV. Consistent with the mouse data, increased FABP4 and FABP5 expression and enhanced extracellular FFA uptake were also demonstrated in human CD8
T
cells in normal and psoriatic skin. These results suggest that FABP4 and FABP5 have a critical role in the maintenance, longevity and function of CD8
T
cells, and suggest that CD8
T
cells use exogenous FFAs and their oxidative metabolism to persist in tissue and to mediate protective immunity.
Inductive power transfer is a practical method for recharging electric vehicles because it is safe, convenient, and reliable. The performance of the magnetic couplers that transfer power determines ...the overall feasibility of a complete system. Circular couplers are the most common topology in the literature; however, they have fundamentally limited coupling. Their flux patterns necessarily limit the operational air gap as well as tolerance to horizontal misalignment. A new polarized coupler topology referred to as a double D (DD) is presented, which overcomes these difficulties. DDs provide a charge zone five times larger than that possible with circular pads for a similar material cost and are smaller. A 0.31-m 2 DD enables 2 kW of power transfer over an oval area measuring 540 mm × 800 mm with a 200-mm air gap. Leakage magnetic fields have been investigated and show that circular and DD couplers operating under similar power transfer conditions produce similar levels. Both topologies can be designed and operated to ensure compliance with international guidelines.
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 ...and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.
During a microbial infection, responding CD8+ T cells give rise to effector cells that provide acute host defense and memory cells that provide sustained protection. An alternative outcome is ...exhaustion, a state of T cell dysfunction that occurs in the context of chronic infections and cancer. Although it is evident that exhausted CD8+ T (TEX) cells are phenotypically and molecularly distinct from effector and memory CD8+ T cells, the factors regulating the earliest events in the differentiation process of TEX cells remain incompletely understood. Here, we performed single-cell RNA-sequencing and single-cell ATAC-sequencing of CD8+ T cells responding to LCMV-Armstrong (LCMV-Arm) or LCMV-Clone 13 (LCMV-Cl13), which result in acute or chronic infections, respectively. Compared to CD8+ T cells that had undergone their first division in response to LCMV-Arm (Div1ARM) cells, CD8+ T cells that had undergone their first division in response to LCMV-Cl13 (Div1CL13) expressed higher levels of genes encoding transcription factors previously associated with exhaustion, along with higher levels of Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2) complex, which mediates epigenetic silencing. Modulation of Ezh2 resulted in altered expression of exhaustion-associated molecules by CD8+ T cells responding to LCMV-Cl13, though the specific cellular and infectious contexts, rather than simply the level of Ezh2 expression, likely determine the eventual outcome. Taken together, these findings suggest that the differentiation paths of CD8+ T cells responding to acute versus chronic infections may diverge earlier than previously appreciated.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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