The identification of stem cells and growth factors as well as the development of biomaterials hold great promise for regenerative medicine applications. However, the therapeutic efficacy of ...regenerative therapies can be greatly influenced by the host immune system, which plays a pivotal role during tissue repair and regeneration. Therefore, understanding how the immune system modulates tissue healing is critical to design efficient regenerative strategies. While the innate immune system is well known to be involved in the tissue healing process, the adaptive immune system has recently emerged as a key player. T-cells, in particular, regulatory T-cells (Treg), have been shown to promote repair and regeneration of various organ systems. In this review, we discuss the mechanisms by which Treg participate in the repair and regeneration of skeletal and heart muscle, skin, lung, bone, and the central nervous system.
Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in ...vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNɣ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.
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•Gene expression profiling mapped systemic macrophage responses to sepsis, MI, and stroke•The tissue microenvironment determined phenotypic adaptions following remote injury•Local proliferation dominated over recruitment in expanding tissue macrophage numbers•Alveolar macrophage priming post MI increased resilience against subsequent pneumonia
Hoyer, Naxerova, et al. generate a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. They find that local injury activates macrophages in remote organs and that these adaptations were damaging or protective in different settings.
NY-ESO-1 or New York esophageal squamous cell carcinoma 1 is a well-known cancer-testis antigen (CTAs) with re-expression in numerous cancer types. Its ability to elicit spontaneous humoral and ...cellular immune responses, together with its restricted expression pattern, have rendered it a good candidate target for cancer immunotherapy. In this review, we provide background information on NY-ESO-1 expression and function in normal and cancerous tissues. Furthermore, NY-ESO-1-specific immune responses have been observed in various cancer types; however, their utility as biomarkers are not well determined. Finally, we describe the immune-based therapeutic options targeting NY-ESO-1 that are currently in clinical trial. We will highlight the recent advancements made in NY-ESO-1 cancer vaccines, adoptive T cell therapy, and combinatorial treatment with checkpoint inhibitors and will discuss the current trends for future NY-ESO-1 based immunotherapy. Cancer treatment has been revolutionized over the last few decades with immunotherapy emerging at the forefront. Immune-based interventions have shown promising results, providing a new treatment avenue for durable clinical responses in various cancer types. The majority of successful immunotherapy studies have been reported in liquid cancers, whereas these approaches have met many challenges in solid cancers. Effective immunotherapy in solid cancers is hampered by the complex, dynamic tumor microenvironment that modulates the extent and phenotype of the antitumor immune response. Furthermore, many solid tumor-associated antigens are not private but can be found in normal somatic tissues, resulting in minor to detrimental off-target toxicities. Therefore, there is an ongoing effort to identify tumor-specific antigens to target using various immune-based modalities. CTAs are considered good candidate targets for immunotherapy as they are characterized by a restricted expression in normal somatic tissues concomitant with a re-expression in solid epithelial cancers. Moreover, several CTAs have been found to induce a spontaneous immune response, NY-ESO-1 being the most immunogenic among the family members. Hence, this review will focus on NY-ESO-1 and discuss the past and current NY-ESO-1 targeted immunotherapeutic strategies.
Summary
A large proportion of memory T cells disseminated throughout the body are non‐recirculating cells whose maintenance and function is regulated by tissue‐specific environmental cues. These ...sessile cells are referred to as tissue‐resident memory T (TRM) cells and similar populations of non‐recirculating cells also exist among unconventional T cells and innate lymphocyte cells. The pool of TRM cells is highly diverse with respect to anatomical positioning, phenotype, molecular regulation and effector function. Nevertheless, certain transcriptional programs are shared and appear as important unifying features for the overall population of TRM cells and tissue‐resident lymphocytes. It is now widely appreciated that TRM cells are a critical component of our immune defense by acting as peripheral sentinels capable of rapidly mobilizing protective tissue immunity upon pathogen recognition. This function is of particular importance in anatomical sites that are not effectively surveilled by blood‐borne memory T cells in absence of inflammation, such as neuronal tissues or epithelial compartments in skin and mucosae. Focusing on the well‐characterized subtype of CD8+ CD69+ CD103+ TRM cells, we will review current concepts on the generation, persistence and function of TRM cells and will summarize commonly used tools to study these cells. Furthermore, we will discuss accumulating data that emphasize localized TRM responses as an important determinant of tissue homeostasis and immune defense in the context of microbiota‐immune interactions, persistent infections and cancer surveillance.
The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the ...liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks. Specifically, the amplitude of clock-controlled genes and BMAL1 chromatin recruitment are drastically altered by KD in the liver, but not in the intestine. KD induces nuclear accumulation of PPARα in both tissues but with different circadian phase. Also, gut and liver clocks respond differently to carbohydrate supplementation to KD. Importantly, KD induces serum and intestinal β-hydroxyl-butyrate levels to robustly oscillate in a circadian manner, an event coupled to tissue-specific cyclic histone deacetylase (HDAC) activity and histone acetylation.
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•KD induces tissue-specific reprogramming of the circadian clock in liver and gut•KD induces an increase in liver BMAL1 chromatin recruitment and amplitude of CCGs•KD drives tissue-specific oscillation of PPARα and its target genes•Oscillation of βOHB in gut and serum parallels gut-specific cycling of H3 acetylation
Tognini et al. reveal how a ketogenic diet (KD) differently affects liver and intestine circadian clocks and drives tissue-specific oscillation of PPARα and its target genes. Serum and intestine βOHB shows a unique diurnal rhythmicity, associated with daily epigenetic changes exclusively in the gut.
RNA viruses, such as poliovirus, have a great evolutionary capacity, allowing them to quickly adapt and overcome challenges encountered during infection. Here we show that poliovirus infection in ...immune-competent mice requires adaptation to tissue-specific innate immune microenvironments. The ability of the virus to establish robust infection and virulence correlates with its evolutionary capacity. We further identify a region in the multi-functional poliovirus protein 2B as a hotspot for the accumulation of minor alleles that facilitate a more effective suppression of the interferon response. We propose that population genetic dynamics enables poliovirus spread between tissues through optimization of the genetic composition of low frequency variants, which together cooperate to circumvent tissue-specific challenges. Thus, intrahost virus evolution determines pathogenesis, allowing a dynamic regulation of viral functions required to overcome barriers to infection.RNA viruses, such as polioviruses, have a great evolutionary capacity and can adapt quickly during infection. Here, the authors show that poliovirus infection in mice requires adaptation to innate immune microenvironments encountered in different tissues.
Abstract
Expression Atlas is EMBL-EBI’s resource for gene and protein expression. It sources and compiles data on the abundance and localisation of RNA and proteins in various biological systems and ...contexts and provides open access to this data for the research community. With the increased availability of single cell RNA-Seq datasets in the public archives, we have now extended Expression Atlas with a new added-value service to display gene expression in single cells. Single Cell Expression Atlas was launched in 2018 and currently includes 123 single cell RNA-Seq studies from 12 species. The website can be searched by genes within or across species to reveal experiments, tissues and cell types where this gene is expressed or under which conditions it is a marker gene. Within each study, cells can be visualized using a pre-calculated t-SNE plot and can be coloured by different features or by cell clusters based on gene expression. Within each experiment, there are links to downloadable files, such as RNA quantification matrices, clustering results, reports on protocols and associated metadata, such as assigned cell types.
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to ...exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
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•β-aminoisobutyric acid (BAIBA) is secreted from PGC-1α-expressing myocytes•BAIBA activates the thermogenic program in white adipocytes via PPARα•Circulating BAIBA levels in mice and humans are increased with exercise•BAIBA is inversely correlated with cardiometabolic risk factors in humans
Roberts et al. use metabolic profiling to identify β-aminoisobutyric acid (BAIBA) as a PGC-1α-responsive small molecule myokine that induces β-oxidation in hepatocytes and the browning of white adipose tissue. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors.
The number of leukocytes present in circulation varies throughout the day, reflecting bone marrow output and emigration from blood into tissues. Using an organism-wide circadian screening approach, ...we detected oscillations in pro-migratory factors that were distinct for specific vascular beds and individual leukocyte subsets. This rhythmic molecular signature governed time-of-day-dependent homing behavior of leukocyte subsets to specific organs. Ablation of BMAL1, a transcription factor central to circadian clock function, in endothelial cells or leukocyte subsets demonstrated that rhythmic recruitment is dependent on both microenvironmental and cell-autonomous oscillations. These oscillatory patterns defined leukocyte trafficking in both homeostasis and inflammation and determined detectable tumor burden in blood cancer models. Rhythms in the expression of pro-migratory factors and migration capacities were preserved in human primary leukocytes. The definition of spatial and temporal expression profiles of pro-migratory factors guiding leukocyte migration patterns to organs provides a resource for the further study of the impact of circadian rhythms in immunity.
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•Leukocyte subsets show time-of-day-dependent migration patterns to organs•This relies on lineage- and tissue-specific oscillations in pro-migratory factors•Loss of circadian clocks in the endothelium or leukocytes ablates rhythmicity•The efficacy of blocking leukocyte migration is time-of-day dependent
Leukocytes continuously circulate throughout the body. He et al. demonstrate that trafficking patterns of major leukocyte subsets occur in a rhythmic manner dependent on the time-of-day-dependent expression of lineage- and tissue-specific factors. This influences the inflammatory response and leukemic tumor burden and translates to the migration behavior of human primary lymphocytes.
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