The gut microbiota and its metabolites have been shown to play a pivotal role in the regulation of metabolic, endocrine and immune functions. Though the exact mechanism of action remains to be fully ...elucidated, available knowledge supports the ability of microbiota-fermented short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, to influence epigenetic and metabolic cascades controlling gene expression, chemotaxis, differentiation, proliferation, and apoptosis in several non-immune and immune cell subsets. While used as preferred metabolic substrates and sources of energy by colonic gut epithelial cells, most recent evidence indicates that these metabolites regulate immune functions, and in particular fine-tune T cell effector, regulatory and memory phenotypes, with direct in vivo consequences on the efficacy of chemotherapy, radiotherapy and immunotherapy. Most recent data also support the use of these metabolites over the course of T cell manufacturing, paving the way for refined adoptive T cell therapy engineering. Here, we review the most recent advances in the field, highlighting in vitro and in vivo evidence for the ability of SCFAs to shape T cell phenotypes and functions.
The generation of immunological memory is a hallmark of adaptive immunity by which the immune system "remembers" a previous encounter with an antigen expressed by pathogens, tumors, or normal ...tissues; and, upon secondary encounters, mounts faster and more effective recall responses. The establishment of T cell memory is influenced by both cell-intrinsic and cell-extrinsic factors, including genetic, epigenetic and environmental triggers. Our current knowledge of the mechanisms involved in memory T cell differentiation has instructed new opportunities to engineer T cells with enhanced anti-tumor activity. The development of adoptive T cell therapy has emerged as a powerful approach to cure a subset of patients with advanced cancers. Efficacy of this approach often requires long-term persistence of transferred T cell products, which can vary according to their origin and manufacturing conditions. Host preconditioning and post-transfer supporting strategies have shown to promote their engraftment and survival by limiting the competition with a hostile tumor microenvironment and between pre-existing immune cell subsets. Although in the general view pre-existing memory can confer a selective advantage to adoptive T cell therapy, here we propose that also "bad memories"-in the form of antigen-experienced T cell subsets-co-evolve with consequences on newly transferred lymphocytes. In this review, we will first provide an overview of selected features of memory T cell subsets and, then, discuss their putative implications for adoptive T cell therapy.
Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for ...proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro-myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- γ-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The urokinase plasminogen activator (uPA) and its receptor (uPAR) exert pleiotropic functions over the course of both physiological and pathological processes. Data generated in deficient mice have ...underlined how uPA not only has a key role in fibrinolysis but also modulates the development of protective immunity. By contrast, uPAR anchors uPA at the cell surface and, in addition to favoring extracellular matrix degradation, regulates cell migration, cell adhesion and cell proliferation, thus influencing the development of inflammatory and immune responses. Here, we review the expression and function of uPA and uPAR, and correlate their role in fibrinolysis with immune, infectious and proliferative disorders. This Review is the second in a series on i
nteractions between haemostasis and inflammation.
Lymphatic endothelial cells (LECs) chemoattract naïve T cells and promote their survival in the lymph nodes, and can cross-present antigens to naïve CD8
T cells to drive their proliferation despite ...lacking key costimulatory molecules. However, the functional consequence of LEC priming of CD8
T cells is unknown. Here, we show that while many proliferating LEC-educated T cells enter early apoptosis, the remainders comprise a long-lived memory subset, with transcriptional, metabolic, and phenotypic features of central memory and stem cell-like memory T cells. In vivo, these memory cells preferentially home to lymph nodes and display rapid proliferation and effector differentiation following memory recall, and can protect mice against a subsequent bacterial infection. These findings introduce a new immunomodulatory role for LECs in directly generating a memory-like subset of quiescent yet antigen-experienced CD8
T cells that are long-lived and can rapidly differentiate into effector cells upon inflammatory antigenic challenge.
The ribonuclease DIS3 is one of the most frequently mutated genes in the hematological cancer multiple myeloma, yet the basis of its tumor suppressor function in this disease remains unclear. Herein, ...exploiting the TCGA dataset, we found that DIS3 plays a prominent role in the DNA damage response. DIS3 inactivation causes genomic instability by increasing mutational load, and a pervasive accumulation of DNA:RNA hybrids that induces genomic DNA double‐strand breaks (DSBs). DNA:RNA hybrid accumulation also prevents binding of the homologous recombination (HR) machinery to double‐strand breaks, hampering DSB repair. DIS3‐inactivated cells become sensitive to PARP inhibitors, suggestive of a defect in homologous recombination repair. Accordingly, multiple myeloma patient cells mutated for DIS3 harbor an increased mutational burden and a pervasive overexpression of pro‐inflammatory interferon, correlating with the accumulation of DNA:RNA hybrids. We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid‐dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.
Synopsis
The ribonuclease DIS3 is frequently mutated in the blood cancer multiple myeloma. Here, DIS3 inactivation is found to cause accumulation of DNA:RNA hybrids, as well as to increases interferon responses and reduce homologous recombination.
DIS3 loss triggers a genome‐wide increase in DNA:RNA hybrids, which in turn leads to DNA fragmentation and genomic instability.
Hybrids accumulation at the sites of DNA damage prevents BRCA1 binding to DNA, impairing homologous recombination‐based DNA repair.
DIS3 loss is associated with increased mutational rate both in vitro and in patient samples with DIS3 mutations.
Myeloma cells derived from patients presenting DIS3 mutations display an intense interferon response.
DIS3 mutation in hematological cancer causes reduced homologous recombination repair, increased mutational burden, and overactivation of inflammatory interferon responses.
Cancer cells are under the surveillance of the host immune system. Nevertheless, a number of immunosuppressive mechanisms allow tumors to escape protective responses and impose immune tolerance. ...Epigenetic alterations are central to cancer cell biology and cancer immune evasion. Accordingly, epigenetic modulating agents (EMAs) are being exploited as anti-neoplastic and immunomodulatory agents to restore immunological fitness. By simultaneously acting on cancer cells, e.g. by changing expression of tumor antigens, immune checkpoints, chemokines or innate defense pathways, and on immune cells, e.g. by remodeling the tumor stroma or enhancing effector cell functionality, EMAs can indeed overcome peripheral tolerance to transformed cells. Therefore, combinations of EMAs with chemo- or immunotherapy have become interesting strategies to fight cancer. Here we review several examples of epigenetic changes critical for immune cell functions and tumor-immune evasion and of the use of EMAs in promoting anti-tumor immunity. Finally, we provide our perspective on how EMAs could represent a game changer for combinatorial therapies and the clinical management of cancer.
High mobility group box 1 (HMGB1) is an abundant chromatin protein that acts as a cytokine when released in the extracellular milieu by necrotic and inflammatory cells. Here, we show that ...extracellular HMGB1 and its receptor for advanced glycation end products (RAGE) induce both migration and proliferation of vessel-associated stem cells (mesoangioblasts), and thus may play a role in muscle tissue regeneration. In vitro, HMGB1 induces migration and proliferation of both adult and embryonic mesoangioblasts, and disrupts the barrier function of endothelial monolayers. In living mice, mesoangioblasts injected into the femoral artery migrate close to HMGB1-loaded heparin-Sepharose beads implanted in healthy muscle, but are unresponsive to control beads. Interestingly, α-sarcoglycan null dystrophic muscle contains elevated levels of HMGB1; however, mesoangioblasts migrate into dystrophic muscle even if their RAGE receptor is disabled. This implies that the HMGB1-RAGE interaction is sufficient, but not necessary, for mesoangioblast homing; a different pathway might coexist. Although the role of endogenous HMGB1 in the reconstruction of dystrophic muscle remains to be clarified, injected HMGB1 may be used to promote tissue regeneration.
Tumors originate from a number of genetic events that deregulate homeostatic mechanisms controlling normal cell behavior. The immune system, devoted to patrol the organism against pathogenic events, ...can identify transformed cells, and in several cases cause their elimination. It is however clear that several mechanisms encompassing both central and peripheral tolerance limit antitumor immunity, often resulting into progressive diseases. Adoptive T‐cell therapy with either allogeneic or autologous T cells can transfer therapeutic immunity. To date, genetic engineering of T cells appears to be a powerful tool for shaping tumor immunity. In this review, we discuss the most recent achievements in the areas of suicide gene therapy, and TCR‐modified T cells and chimeric antigen receptor gene‐modified T cells. We provide an overview of current strategies aimed at improving the safety and efficacy of these approaches, with an outlook on prospective developments.
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