transforming-growth-factor-beta and Virus-Diseases

Cytokines are soluble and membrane-bound factors that dictate immune responses. Dogmatically, cytokines are divided into families that promote type 1 cell-mediated immune responses (e.g., IL-12) or type 2 humoral responses (e.g., IL-4), each capable of antagonizing the opposing family of cytokines. The discovery of additional families of cytokines (e.g., IL-17) has added complexity to this model, but it was the realization that immune responses frequently comprise mixtures of different types of cytokines that dismantled this black-and-white paradigm. In some cases, one type of response may dominate these mixed milieus in disease pathogenesis and thereby present a clear therapeutic target. Alternatively, synergistic or blended cytokine responses may obfuscate the origins of disease and perplex clinical decision making. Most immune cells express receptors for many types of cytokines and can mediate a myriad of functions important for tolerance, immunity, tissue damage, and repair. In this review, we will describe the unconventional effects of a variety of cytokines on the activity of a prototypical type 1 effector, the natural killer (NK) cell, and discuss how this may impact the contributions of these cells to health and disease.

Topics: Cytokines; Humans; Interleukins; Killer Cells, Natural; Transforming Growth Factor beta; Virus Diseases

PML is a tumour suppressor inactivated in Acute Promyelocytic Leukaemia (APL). PML is the essential component of a subnuclear structure called the PML nuclear body (PML-NB), which is disrupted in APL. By targeting different cellular proteins to this structure, PML can either hamper or potentiate their functions. The PML transcript undergoes alternative splicing to generate both nuclear and cytoplasmic isoforms. Most of the research in this field has focused its attention on studying nuclear PML. Nevertheless, new exciting studies show that cytoplasmic PML may control essential cellular functions, thus opening new avenues for investigation.

Topics: Active Transport, Cell Nucleus; Adaptor Proteins, Signal Transducing; Alternative Splicing; Animals; Cell Cycle; Cell Nucleus; Cytoplasm; Gene Expression Regulation, Neoplastic; Humans; Interferons; Leukemia, Promyelocytic, Acute; Membrane Proteins; Neoplasm Proteins; Nuclear Proteins; Oncogene Proteins, Fusion; Promyelocytic Leukemia Protein; Protein Isoforms; Signal Transduction; Transcription Factors; Transforming Growth Factor beta; Tumor Suppressor Proteins; Virus Diseases

Regulatory/suppressor cells have become rehabilitated and respectable. They returned as regulators of autoimmunity, but are now acknowledged to critically influence immunity to foreign antigens, such as those found on microbes. This review describes the principal types of regulatory cells that influence immunity to microbes, focusing on viruses. We discuss both the merits and downside of the Treg response during infection. The mechanisms by which Treg are induced, recognize microbes, and exert their function is also discussed. Finally, we examine approaches that might prove useful to manipulate regulatory cell response against infections.

Topics: Animals; Antigens, Viral; CD8-Positive T-Lymphocytes; Humans; Immunity, Innate; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Virus Diseases; Viruses

shRNA lentiviral vectors are extensively used for gene knockdowns in mammalian cells, and non-target shRNAs typically are considered the proper experimental control for general changes caused by RNAi. However, the effects of non-target lentivirus controls on the modulation of cell signaling pathways remain largely unknown. In this study, we evaluated the effect of control lentiviral transduction on oxytocin receptor (OXTR) expression through the ERK/MAPK pathway in mouse and human skeletal muscle cells, on myogenic activity, and in vivo on mouse muscle regeneration. Furthermore, we mined published data for the influence of viral infections on OXTR levels in human populations and found that unrelated viral pathologies have a common consequence: diminished levels of OXTR.. We examined the change in OXTR mRNA expression upon transduction with control and Smad3-targeting viral vectors through real time RT-PCR and Western blotting, and confirmed with immunofluorescence. Changes in Smad3 and OXTR expression were examined both in vitro with mouse and human myoblasts and in vivo in mouse satellite cells. The general effects of viral infections on OXTR downregulation in humans were also examined by analyzing published Gene Expression Omnibus (GEO) datasets. The change in myoblast myogenic activity caused by the viral transduction (the percent of Pax7 + Ki67+ cells) was examined by immunofluorescence.. Results shown in this work establish that lentiviral control vectors significantly downregulate OXTR expression at mRNA and protein levels and diminish key downstream effectors of OXTR, ERK signaling, reducing the myogenic proliferation of infected cells. This effect is evolutionarily conserved between mouse and human myogenic cells, and it manifests in satellite cells after control lentiviral transduction of mice in vivo. Furthermore, an examination of published datasets uncovered similar OXTR downregulation in humans that are afflicted with different viral infections. Additionally, cells transduced with Smad3-targeting shRNA downregulate OXTR even more than cells transduced with control viruses.. Our work suggests that experimental cohorts transduced with control viruses may not behave the same as un-transduced cells and animals, specifically that control viral vectors significantly change the intensity of key cell-signaling pathways, such as OXTR/ERK. Our results further demonstrate that lentiviral transduction significantly decreases myogenic proliferation and suggest that viral infections in general may play a role in decreasing muscle health and regeneration, a decline in metabolic health, and a lower sense of well-being, as these rely on effective OXTR signaling. Additionally, our data suggest pathway crosstalk between TGF-β/pSmad3 and OXTR, implying that sustained attenuation of the TGF-β/pSmad3 pathway will reduce pro-regenerative OXTR/pERK signaling.

Topics: Animals; Cells, Cultured; Down-Regulation; Evolution, Molecular; Humans; Lentivirus; Mice; Mice, Inbred C57BL; Myoblasts; Receptors, Oxytocin; Satellite Cells, Skeletal Muscle; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta; Virus Diseases

Following microbial pathogen invasion, one of the main challenges for the host is to rapidly control pathogen spreading to avoid vital tissue damage. Here we report that an effector CD8(+) T-cell population that expresses the marker NK1.1 undergoes delayed contraction and sustains early anti-microbial protection. NK1.1(+) CD8(+) T cells are derived from CD8(+) T cells during priming, and their differentiation is inhibited by transforming growth factor-β signalling. After their own contraction phase, they form a distinct pool of KLRG1 CD127 double-positive memory T cells and rapidly produce both interferon-γ and granzyme B, providing significant pathogen protection in an antigen-independent manner within only a few hours. Thus, by prolonging the CD8(+) T-cell response at the effector stage and by expressing exacerbated innate-like features at the memory stage, NK1.1(+) cells represent a distinct subset of CD8(+) T cell that contributes to the early control of microbial pathogen re-infections.

Topics: Animals; Antigens, Ly; Bacterial Infections; Bone Marrow Cells; CD8-Positive T-Lymphocytes; Cell Differentiation; Female; Flow Cytometry; Granzymes; Immunity, Innate; Immunologic Memory; Interferon-gamma; Interleukin-15; Interleukin-7 Receptor alpha Subunit; Listeria monocytogenes; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; NK Cell Lectin-Like Receptor Subfamily B; Peptides; Phenotype; Signal Transduction; Transforming Growth Factor beta; Virus Diseases

Type 1 diabetes (T1D) is an autoimmune disease resulting from T cell-mediated destruction of insulin-producing β cells, and viral infections can prevent the onset of disease. Invariant natural killer T cells (iNKT cells) exert a regulatory role in T1D by inhibiting autoimmune T cell responses. As iNKT cell-plasmacytoid dendritic cell (pDC) cooperation controls viral replication in the pancreatic islets, we investigated whether this cellular cross talk could interfere with T1D development during viral infection. Using both virus-induced and spontaneous mouse models of T1D, we show that upon viral infection, iNKT cells induce TGF-β-producing pDCs in the pancreatic lymph nodes (LNs). These tolerogenic pDCs convert naive anti-islet T cells into Foxp3(+) CD4(+) regulatory T cells (T reg cells) in pancreatic LNs. T reg cells are then recruited into the pancreatic islets where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8(+) T cells, thereby preventing T1D development in both T1D models. These findings reveal a crucial cooperation between iNKT cells, pDCs, and T reg cells for prevention of T1D by viral infection.

Topics: Animals; Antigens, Surface; Apoptosis Regulatory Proteins; B7-1 Antigen; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Cell Communication; Dendritic Cells; Diabetes Mellitus, Type 1; Interleukin-10; Islets of Langerhans; Lymph Nodes; Lymphocyte Activation; Membrane Glycoproteins; Mice; Natural Killer T-Cells; Peptides; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Virus Diseases

Topics: Animals; Asthma; Bronchial Provocation Tests; Cells, Cultured; Histamine; In Vitro Techniques; Inflammation; Interleukin-1; Interleukin-11; Interleukin-4; Lung; Mice; Mice, Inbred BALB C; Respiratory Tract Infections; Transforming Growth Factor beta; Virus Diseases