ABSTRACT
Autoreactive T cells with the phenotype and function of different memory subsets are present in patients who developed type 1 diabetes (TID). According to the progressive differentiation model, memory subsets generate from naïve precursors in a linear and unidirectional path depending on the strength and quality of stimulatory signals. By observing human naïve T cells in contact with GAD65 loaded autologous dendritic cells, we observed that approximately 10% of cells divided with the plane of cell division parallel to the one of the immune synapse, causing phenotypic asymmetries in the proximal and distal daughter T cells. After the first T cell division, proximal and distal daughter T cells showed different phenotype, metabolic signature and commitment to differentiate towards long-lived memory T cells or T cells with effector function. Subjects with or without T1D showed a similar frequency of asymmetric T cell division (ATCD) for autoantigens and recall antigens specific T cells, however the frequency of ATCD is significantly increased in autoreactive T cells in patients with T1D when IL-7 was added to the culture. An increased upregulation of GLUT1 in response to IL-7 in patients with T1D was related to the rate of ATCD. Our results showed that ATCD is associated with an early divergence in the differentiation fate of naïve T cells specific for GAD65 during first antigen encounter.
Subject(s)
Diabetes Mellitus, Type 1 , Autoantigens , Cell Differentiation , Cell Division , Glucose Transporter Type 1/metabolism , Humans , Immunologic Memory , Interleukin-7/metabolism , Memory T Cells , T-Lymphocyte SubsetsABSTRACT
Cornelia de Lange syndrome (CdLS), which is reported to affect â¼1 in 10 000 to 30 000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition. CdLS can result from mutations in at least five genes: nipped-B-like protein, structural maintenance of chromosomes 1A, structural maintenance of chromosomes 3, RAD21 cohesin complex component and histone deacetylase 8 (HDAC8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development. Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells (NSCs) and in vertebrate (Danio rerio) brain development by knockdown and chemical inhibition experiments. Underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs or in zebrafish embryos.
Subject(s)
Cell Cycle Proteins/physiology , Chromosomal Proteins, Non-Histone/physiology , De Lange Syndrome/genetics , Histone Deacetylases/genetics , Animals , Cell Cycle Proteins/genetics , Cell Differentiation/genetics , Cell Differentiation/physiology , Chromosomal Proteins, Non-Histone/genetics , De Lange Syndrome/physiopathology , Gene Expression Regulation/genetics , Histone Deacetylases/metabolism , Histone Deacetylases/physiology , Male , Mice , Mice, Inbred C57BL , Mutation/genetics , Neural Stem Cells/physiology , Neurons/physiology , Phenotype , Repressor Proteins/genetics , Zebrafish , Zebrafish Proteins , CohesinsABSTRACT
PURPOSE OF REVIEW: An increasing body of evidence indicates that bio-energetic metabolism of activated T cells is a potential target to control the autoimmune response in type 1 diabetes (T1D). RECENT FINDINGS: T-cell activation and proliferation is linked to the cell capacity to provide sufficient energy and biosynthesis molecules to support T-cell growth and division. This makes T cells susceptible to metabolic inhibition for the control of the T-cell response. There is a wide therapeutic arsenal of metabolic inhibitors, including novel classes of drugs that have become recently available. With the current knowledge and availability of metabolic inhibitors, we are now in the position to design a metabolic inhibition strategy to determine whether targeting of autoreactive T cells is an effective strategy to control the process of ß-cell destruction in T1D.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1/drug therapy , Insulin-Secreting Cells/immunology , T-Lymphocytes/metabolism , Animals , Diabetes Mellitus, Type 1/immunology , Humans , Lymphocyte Activation , Metabolic Networks and Pathways , T-Lymphocytes/immunologyABSTRACT
Stem memory T cells (Tscm) constitute the earliest developmental stage of memory T cells, displaying stem cell-like properties, such as self-renewal capacity. Their superior immune reconstitution potential has sparked interest in cancer immune therapy, vaccine development, and immune reconstitution, whereas their role in autoimmunity is largely unexplored. Here we show that autoreactive CD8+ Tscm specific for ß-cell antigens GAD65, insulin, and IGRP are present in patients with type 1 diabetes (T1D). In vitro, the generation of autoreactive Tscm from naive precursors required the presence of the homeostatic cytokine interleukin-7 (IL-7). IL-7 promotes glucose uptake via overexpression of GLUT1 and upregulation of the glycolytic enzyme hexokinase 2. Even though metabolism depends on glucose uptake, the subsequent oxidation of pyruvate in the mitochondria was necessary for Tscm generation from naive precursors. In patients with T1D, high expression of GLUT1 was a hallmark of circulating Tscm, and targeting glucose uptake via GLUT1 using the selective inhibitor WZB117 resulted in inhibition of Tscm generation and expansion. Our results suggest that autoreactive Tscm are present in patients with T1D and can be selectively targeted by inhibition of glucose metabolism.
Subject(s)
Autoimmunity/immunology , CD8-Positive T-Lymphocytes/immunology , Diabetes Mellitus, Type 1/immunology , Lymphoid Progenitor Cells/immunology , T-Lymphocyte Subsets/immunology , Adolescent , Adult , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Child , Diabetes Mellitus, Type 1/metabolism , Female , Glucose/metabolism , Glucose Transporter Type 1/metabolism , Glucose-6-Phosphatase/immunology , Glutamate Decarboxylase/immunology , Hexokinase/metabolism , Humans , Hydroxybenzoates/pharmacology , Immunologic Memory/immunology , In Vitro Techniques , Insulin/immunology , Interleukin-7/immunology , Lymphopoiesis/drug effects , Male , Middle Aged , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/metabolism , Up-RegulationABSTRACT
Activation and maintenance of the T cell response occurs concurrently with metabolic reprogramming. This ensures the T cell response is supported by sufficient energy and substrates necessary for cell survival, growth and proliferation. Different metabolic programs are associated with differentiation into different cell subsets, effector function and development of long-lasting memory. This provides an opportunity to improve the T cell response through manipulation of metabolism, which is instrumental to ameliorate the current protocols for cancer immunotherapy. Using drugs and molecules targeting selective metabolic pathways it is now possible to generate T cells that can mount a durable and stable anti-tumor response. On the other hand, cancer cells can take advantage of the metabolic requirements of T cells to evade the immune response. In this brief review we discuss recent findings of T cell metabolism in quiescence and activation, how the tumor microenvironment can affect T cell metabolism, and how T cell metabolism can be manipulated to improve the T cell response to tumors.