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 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 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.

A unique T cell subset described as CD4loCD40+ T cells (TCD40) in human type 1 diabetes

2007 ◽  
Vol 124 (2) ◽  
pp. 138-148 ◽  
Author(s):  
Dan M. Waid ◽  
Rebecca J. Wagner ◽  
Amy Putnam ◽  
Gisela M. Vaitaitis ◽  
Nathan D. Pennock ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Subset ◽  
T Cell Subset ◽  
Human Type ◽  
Human Type 1 Diabetes

scholarly journals HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression1

2018 ◽  
Author(s):  
Jennifer Schloss ◽  
Riyasat Ali ◽  
Jeremy J. Racine ◽  
Harold D. Chapman ◽  
David V. Serreze ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Mouse Model ◽  
Disease Onset ◽  
Cell Subset ◽  
Class I ◽  
Class I Mhc ◽  
Insulin Expression

ABSTRACTType 1 diabetes (T1D) is characterized by T cell-mediated destruction of the insulin-producing βcells of the pancreatic islets. Among the loci associated with T1D risk, those most predisposing are found in the MHC region. HLA-B*39:06 is the most predisposing class I MHC allele and is associated with an early age of onset. To establish an NOD mouse model for the study of HLA-B*39:06, we expressed it in the absence of murine class I MHC. HLA-B*39:06 was able to mediate the development of CD8 T cells, support lymphocytic infiltration of the islets, and confer T1D susceptibility. Because reduced thymic insulin expression is associated with increased T1D risk in patients, we incorporated this in our model as well, finding that HLA-B*39:06-transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset and a higher overall prevalence as compared to littermates with typical thymic insulin expression. This was despite virtually indistinguishable blood insulin levels, T cell subset percentages, and TCR Vβ family usage, indicating that reduced thymic insulin expression does not impact T cell development on a global scale. Rather, we propose that it allows the thymic escape of insulin-reactive HLA-B*39:06-restricted T cells which participate in β cell destruction. We also found that in mice expressing either HLA-B*39:06 or HLA-A*02:01 in the absence of murine class I MHC, HLA transgene identity alters TCR Vβ usage, which may contribute to varying diabetogenic CD8 T cell repertoires in the presence of different HLA class I alleles.

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