scholarly journals Increased islet antigen–specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes–protective haplotype

2020 ◽  
Vol 5 (44) ◽  
pp. eaax8767 ◽  
Author(s):  
Xiaomin Wen ◽  
Junbao Yang ◽  
Eddie James ◽  
I-Ting Chow ◽  
Helena Reijonen ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cells ◽  
Interleukin 4 ◽  
Specific Class ◽  
Protective Haplotype ◽  
Specific Effector ◽  
Islet Antigen

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP)–specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127−FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen–specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope–specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10–producing T effectors and CD25+CD127−FOXP3+ regulatory T cells.

scholarly journals Type 1 diabetes progression is associated with loss of CD3+CD56+ regulatory T cells that control CD8+ T-cell effector functions

2020 ◽  
Vol 2 (2) ◽  
pp. 142-152 ◽  
Author(s):  
Giuseppe Terrazzano ◽  
Sara Bruzzaniti ◽  
Valentina Rubino ◽  
Marianna Santopaolo ◽  
Anna Teresa Palatucci ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cell ◽  
Effector Functions ◽  
Diabetes Progression ◽  
Cell Effector

scholarly journals IPEX as a Result of Mutations in FOXP3

2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Hans J. J. van der Vliet ◽  
Edward E. Nieuwenhuis
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Subset ◽  
Clinical Implications ◽  
Immune Homeostasis ◽  
Immunoregulatory Cells ◽  
Autoimmune Phenomena

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutations in theFOXP3gene that result in the defective development ofCD4+CD25+regulatory T cells which constitute an important T cell subset involved in immune homeostasis and protection against autoimmunity. Their deficiency is the hallmark of IPEX and leads to severe autoimmune phenomena including autoimmune enteropathy, dermatitis, thyroiditis, and type 1 diabetes, frequently resulting in death within the first 2 years of life. Apart from its clinical implications, IPEX illustrates the importance of immunoregulatory cells such asCD4+CD25+regulatory T cells.

scholarly journals Advanced Approaches in Immunotherapy for the Treatment of Type 1 Diabetes Mellitus

EMJ Diabetes ◽  
2020 ◽  
Author(s):  
Bryan Ceballos ◽  
Michael Alexander ◽  
Jonathan R. T. Lakey
Keyword(s):  
Diabetes Mellitus ◽  
T Cells ◽  
Type 1 Diabetes ◽  
Immune System ◽  
T Cell ◽  
Regulatory T Cells ◽  
Type 1 Diabetes Mellitus ◽  
T Cell Receptors ◽  
Cell Receptors

The cure for Type 1 diabetes mellitus (T1DM) is likely to require an effective strategy for suppressing or evading the immune system. When considering curative treatments, it is almost inevitable to consider novel ways of inducing tolerogenicity to insulin-producing β cells. While the main mechanism of achieving tolerogenicity is restoring regulatory T cell (CD4+CD25+Fox3+) to effector T-cell (CD4+Fox3-) homeostasis, the means of achieving this are multifarious. The advent of a glucocorticoid-free immunosuppressive regimen was an early indication of how immunotherapeutics affect β-cell function. As newer biologics are developed, suppressing the immune system continues to become more specific and dynamic. An ever-evolving field of immunology has shifted the paradigm of how T1DM is understood, and the repurposing of T-cell-based biotechnology has the potential to change the way that it is treated. Regulatory T cells can be bioengineered to express T-cell receptors with affinity for peptide–human leukocyte antigen complexes that are frequently encountered in T1DM. Exosomes with embedded T-cell receptors can be isolated from regulatory T cells for use as an off-the-shelf therapy.

Distinct Phenotypes of Islet Antigen-Specific CD4+ T Cells Among the 3 Subtypes of Type 1 Diabetes

2020 ◽  
Vol 105 (10) ◽  
pp. 3141-3151 ◽  
Author(s):  
Daisuke Chujo ◽  
Akitsu Kawabe ◽  
Maya Matsushita ◽  
Nobuyuki Takahashi ◽  
Chiharu Tsutsumi ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Th2 Cells ◽  
Cell Phenotype ◽  
Islet Antigen ◽  
Ex Vivo Assay

Abstract Context Type 1 diabetes (T1D) is classified into 3 subtypes: acute-onset (AT1D), slowly progressive (SP1D), and fulminant (FT1D). The differences in the type of cellular autoimmunity within each subtype remain largely undetermined. Objective To determine the type and frequency of islet antigen-specific CD4+ T cells in each subtype of T1D. Participants Twenty patients with AT1D, 17 with SP1D, 18 with FT1D, and 17 persons without diabetes (ND). Methods We performed an integrated assay to determine cellular immune responses and T-cell repertoires specific for islet antigens. This assay included an ex vivo assay involving a 48-hour stimulation of peripheral blood mononuclear cells with antigen peptides and an expansion assay involving intracytoplasmic cytokine analysis. Results The results of the ex vivo assay indicated that glutamic acid decarboxylase 65 (GAD65)-specific interleukin-6 and interferon-inducible protein-10 (IP-10) responses and preproinsulin (PPI)-specific IP-10 responses were significantly upregulated in AT1D compared with those of ND. Furthermore, GAD65- and PPI-specific granulocyte colony-stimulating factor responses were significantly upregulated in FT1D. Expansion assay revealed that GAD65- and PPI-specific CD4+ T cells were skewed toward a type 1 helper T (Th1)- cell phenotype in AT1D, whereas GAD65-specific Th2 cells were prevalent in SP1D. GAD65-specific Th1 cells were more abundant in SP1D with human leukocyte antigen-DR9 than in SP1D without DR9. FT1D displayed significantly less type 1 regulatory T (Tr1) cells specific for all 4 antigens than ND. Conclusions The phenotypes of islet antigen-specific CD4+ T cells differed among the three T1D subtypes. These distinct T-cell phenotypes may be associated with the manner of progressive β-cell destruction.

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