scholarly journals Two to Tango: Dialogue between Adaptive and Innate Immunity in Type 1 Diabetes

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Lin Sun ◽  
Shugang Xi ◽  
Guangyu He ◽  
Zhuo Li ◽  
Xiaokun Gang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Autoimmune Disorder ◽  
Innate Immune ◽  
Therapeutic Interventions ◽  
T Cell Subsets ◽  
And Function

Type 1 diabetes mellitus (T1DM) is a long-term and chronic autoimmune disorder, in which the immune system attacks the pancreatic β-cells. Both adaptive and innate immune systems are involved in T1DM development. Both B-cells and T-cells, including CD4+ and CD8+ T-cells, as well as other T-cell subsets, could affect onset of autoimmunity. Furthermore, cells involved in innate immunity, including the macrophages, dendritic cells, and natural killer (NK) cells, could also accelerate or decelerate T1DM development. In this review, the crosstalk and function of immune cells in the pathogenesis of T1DM, as well as the corresponding therapeutic interventions, are discussed.

scholarly journals Expansion of Functional Regulatory T Cells Using Soluble RAGE Prevents Type 1 Diabetes

2020 ◽  
Author(s):  
Sherman S. Leung ◽  
Danielle J. Borg ◽  
Domenica A. McCarthy ◽  
Tamar E. Boursalian ◽  
Justen Cracraft ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Soluble Rage ◽  
Human T Cells ◽  
Glycation End Products ◽  
Term Administration ◽  
Pancreatic Lymph Nodes ◽  
And Function

AbstractType 1 diabetes (T1D) is an autoimmune disease with no cure. Therapeutic translation has been hampered by preclinical reproducibility. Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent centers. Treatment with sRAGE increased regulatory T cells (Tregs) within islets, pancreatic lymph nodes and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE using knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy at multiple research centers and in human T cells.

scholarly journals Making the Most of Major Histocompatibility Complex Molecule Multimers: Applications in Type 1 Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Greg S. Gojanovich ◽  
Paul R. Hess
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Subsets ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Pancreatic Islets Of Langerhans

Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producingβcells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

scholarly journals Immune interventions to preserve β cell function in type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Mario R Ehlers
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Regulatory T Cells ◽  
Immune Modulation ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell

Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to destruction of pancreatic β cells, lifelong dependence on insulin, and increased morbidity and mortality from diabetes-related complications. Preservation of residual β cells at diagnosis is a major goal because higher levels of endogenous insulin secretion are associated with better short- and long-term outcomes. For the past 3 decades, a variety of immune interventions have been evaluated in the setting of new-onset T1D, including nonspecific immunosuppression, pathway-specific immune modulation, antigen-specific therapies, and cellular therapies. To date, no single intervention has produced durable remission off therapy in most treated patients, but the field has gained valuable insights into disease mechanisms and potential immunologic correlates of success. In particular, T-cell–directed therapies, including therapies that lead to partial depletion or modulation of effector T cells and preservation or augmentation of regulatory T cells, have shown the most success and will likely form the backbone of future approaches. The next phase will see evaluation of rational combinations, comprising one or more of the following: an effector T-depleting or -modulating drug, a cytokine-based tolerogenic (regulatory T-cells–promoting) agent, and an antigen-specific component. The long term goal is to reestablish immunologic tolerance to β cells, thereby preserving residual β cells early after diagnosis or enabling restoration of β-cell mass from autologous stem cells or induced neogenesis in patients with established T1D.

scholarly journals T Cells Cause Acute Immunopathology and Are Required for Long-Term Survival in Mouse Adenovirus Type 1-Induced Encephalomyelitis

2003 ◽  
Vol 77 (18) ◽  
pp. 10060-10070 ◽  
Author(s):  
Martin L. Moore ◽  
Corrie C. Brown ◽  
Katherine R. Spindler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Adenovirus Type ◽  
T Cell Subsets ◽  
Class I ◽  
Term Survival ◽  
Immunodeficient Mice

ABSTRACT Infection of adult C57BL/6 (B6) mice with mouse adenovirus type 1 (MAV-1) results in dose-dependent encephalomyelitis. Utilizing immunodeficient mice, we analyzed the roles of T cells, T-cell subsets, and T-cell-related functions in MAV-1-induced encephalomyelitis. T cells, major histocompatibility complex (MHC) class I, and perforin contributed to acute disease signs at 8 days postinfection (p.i.). Acute MAV-1-induced encephalomyelitis was absent in mice lacking T cells and in mice lacking perforin. Mice lacking α/β T cells had higher levels of infectious MAV-1 at 8 days, 21 days, and 12 weeks p.i., and these mice succumbed to MAV-1-induced encephalomyelitis at 9 to 16 weeks p.i. Thus, α/β T cells were required for clearance of MAV-1. MAV-1 was cleared in mice lacking perforin, MHC class I or II, CD4+ T cells, or CD8+ T cells. Our results are consistent with a model in which either CD8+ or CD4+ T cells are sufficient for clearance of MAV-1. Furthermore, perforin contributed to MAV-1 disease but not viral clearance. We have established two critical roles for T cells in MAV-1-induced encephalomyelitis. T cells caused acute immunopathology and were required for long-term host survival of MAV-1 infection.

Innate immune receptors in type 1 diabetes: the relationship to cell death-associated inflammation

2020 ◽  
Vol 48 (3) ◽  
pp. 1213-1225 ◽  
Author(s):  
Tae Kang Kim ◽  
Myung-Shik Lee
Keyword(s):  
Innate Immunity ◽  
Type 1 Diabetes ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Innate Immune ◽  
Therapeutic Modalities ◽  
Immune Receptors ◽  
Molecular Patterns

The importance of innate immunity in host defense and inflammatory responses has been clearly demonstrated after the discovery of innate immune receptors such as Toll-like receptors (TLRs) or Nucleotide-binding oligomerization domain-containing protein (Nod)-like receptors (NLRs). Innate immunity also plays a critical role in diverse pathological conditions including autoimmune diseases such as type 1 diabetes (T1D). In particular, the role of a variety of innate immune receptors in T1D has been demonstrated using mice with targeted disruption of such innate immune receptors. Here, we discuss recent findings showing the role of innate immunity in T1D that were obtained mostly from studies of genetic mouse models of innate immune receptors. In addition, the role of innate immune receptors involved in the pathogenesis of T1D in sensing death-associated molecular patterns (DAMPs) released from dead cells or pathogen-associated molecular patterns (PAMPs) will also be covered. Elucidation of the role of innate immune receptors in T1D and the nature of DAMPs sensed by such receptors may lead to the development of new therapeutic modalities against T1D.

scholarly journals Unsupervised clustering reveals a unique Treg profile in slow progressors to type 1 diabetes

2021 ◽  
Author(s):  
Joanne Boldison ◽  
Anna E Long ◽  
Rachel J Aitken ◽  
Isabel V Wilson ◽  
Claire Megson ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Cd4 T Cells ◽  
Unsupervised Clustering ◽  
Slow Progressors ◽  
Healthy Donors ◽  
Treg Suppression ◽  
And Gender ◽  
And Function

AbstractObjectiveTo profile CD4+ regulatory T cells (Tregs) in a well-characterised cohort of slow progressors to type 1 diabetes, individuals positive for multiple islet autoantibodies who remain diabetes-free for at least 10 years.Research Design and MethodsPeripheral blood samples were obtained from extreme slow progressor individuals (n=8), with up to 32 years follow-up, and age and gender-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment, and was individually evaluated in the data analysis. PBMCs were isolated, from donors, and to assess frequency, phenotype and function of Tregs, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, FlowSOM and CITRUS, was used to evaluate Treg phenotypes.ResultsTreg mediated suppression of CD4+ effector T cells, from slow progressors was significantly impaired, compared to healthy donors (P<0.05). Effector CD4 T cells, from slow progressors, were more responsive to Treg suppression, compared to healthy donors, demonstrated by increased suppression of CD25 expression on effector CD4 T cells (P<0.05). Unsupervised clustering on memory CD4 T cells, from slow progressors, showed an increased frequency of activated-memory CD4 Tregs associated with increased expression of GITR, compared to healthy donors (P<0.05). The participant with a raised HbA1c had a different Treg profile, compared to slow progressors and the matched controls.ConclusionsCD4+ Tregs from slow progressor individuals have a unique Treg signature. This report highlights the need for further study of Treg heterogeneity in individuals at-risk of developing type 1 diabetes.

scholarly journals A high glycemic burden relates to functional and metabolic alterations of human monocytes in patients with type 1 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Kathrin Thiem ◽  
Xanthe A.M.H. van Dierendonck ◽  
Anna W.M. Janssen ◽  
Joline P. Boogaard ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Innate Immune System ◽  
Ex Vivo ◽  
Innate Immune ◽  
Transcriptome Profile ◽  
Inflammatory Gene Expression ◽  
Patients With Diabetes ◽  
And Function ◽  
Glycolytic Rate

Diabetes mellitus is associated with increased cardiovascular risk and higher occurrence of infections. These complications suggest altered responses of the innate immune system. Recent studies have shown that energy metabolism of monocytes is crucial in determining their functionality. Here we investigate whether monocyte metabolism and function are changed in patients with diabetes and aim to identify diabetes-associated factors driving these alterations. Patients with type 1 diabetes (T1D) (n=41) and healthy age-, sex- and BMI-matched controls (n=20) were recruited. Monocytes were isolated from peripheral blood to determine immune functionality, metabolic responses and transcriptome profile. Upon <i>ex vivo</i> stimulation with TLR-4 or TLR-2 agonists, monocytes of patients with T1D secreted lower levels of various cytokines and showed lower glycolytic rates in comparison to monocytes isolated from matched controls. Stratification based on HbA<sub>1c</sub> levels revealed that lower cytokine secretion was coupled to higher glycolytic rate of monocytes in patients with higher glycemic burden. Circulating monocytes displayed an enhanced inflammatory gene expression profile associated with high glycemic burden. These results suggest that a high glycemic burden in patients with T1D is related to expression of inflammatory genes of monocytes and is associated with an impaired relationship between metabolism and inflammatory function upon activation.

Sign in / Sign up

Export Citation Format

Share Document