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

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.

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Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients

Journal of Experimental Medicine ◽

10.1084/jem.20111187 ◽

2012 ◽

Vol 209 (1) ◽

pp. 51-60 ◽

Cited By ~ 368

Author(s):

Ken T. Coppieters ◽

Francesco Dotta ◽

Natalie Amirian ◽

Peter D. Campbell ◽

Thomas W.H. Kay ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

Direct Proof ◽

Hla Class I ◽

Cd8 T Cell ◽

Class I ◽

Β Cell ◽

Cell Reactivity

A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8+ insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2–expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in situ tetramer staining. Both single and multiple CD8 T cell autoreactivities were detected within individual islets in a subset of patients up to 8 yr after clinical diagnosis. Pathological features such as HLA class I hyperexpression and insulitis were specific for T1D and persisted in a small portion of the patients with longstanding disease. Insulitic lesions consistently presented in a multifocal pattern with varying degrees of infiltration and β cell loss across affected organs. Our observations provide the first direct proof for islet autoreactivity within human islets and underscore the heterogeneous and chronic disease course.

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Regulatory T Cells Selectively Control CD8+ T Cell Effector Pool Size via IL-2 Restriction

The Journal of Immunology ◽

10.4049/jimmunol.1101649 ◽

2011 ◽

Vol 187 (6) ◽

pp. 3186-3197 ◽

Cited By ~ 53

Author(s):

Wolfgang Kastenmuller ◽

Georg Gasteiger ◽

Naeha Subramanian ◽

Tim Sparwasser ◽

Dirk H. Busch ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cd8 T Cell ◽

Pool Size ◽

Cell Effector

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Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Journal of Clinical Investigation ◽

10.1172/jci126595 ◽

2019 ◽

Vol 130 (1) ◽

pp. 480-490 ◽

Cited By ~ 15

Author(s):

Alice E. Wiedeman ◽

Virginia S. Muir ◽

Mario G. Rosasco ◽

Hannah A. DeBerg ◽

Scott Presnell ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

Cd8 T Cell ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

Slow Type ◽

Diabetes Progression

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EBV-Specific CD8+T Cell Reactivation in Transplant Patients Results in Expansion of CD8+Type-1 Regulatory T Cells

American Journal of Transplantation ◽

10.1111/j.1600-6143.2007.01740.x ◽

2007 ◽

Vol 7 (5) ◽

pp. 1215-1223 ◽

Cited By ~ 28

Author(s):

I. Popescu ◽

C. Macedo ◽

K. Abu-Elmagd ◽

R. Shapiro ◽

Y. Hua ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cd8 T Cell ◽

Cell Reactivation ◽

Transplant Patients

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IPEX as a Result of Mutations in FOXP3

Clinical and Developmental Immunology ◽

10.1155/2007/89017 ◽

2007 ◽

Vol 2007 ◽

pp. 1-5 ◽

Cited By ~ 86

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.

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

EMJ Diabetes ◽

10.33590/emjdiabet/20-00062 ◽

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.

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CD5 expressing CD8+ T cell subsets differ between children with Type 1 Diabetes and controls

10.22541/au.161340217.73911085/v1 ◽

2021 ◽

Author(s):

Josefine Wadenpohl ◽

Julia Seyfarth ◽

Paul Hehenkamp ◽

Maximilian Hoffmann ◽

Sebastian Kummer ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

Type 1 Diabetes ◽

T Cell ◽

B Cell ◽

Quantitative Pcr ◽

T Cell Activation ◽

Cell Activation ◽

Cd8 T Cell

Different lymphocyte subsets are involved in autoimmune pathogenesis of Type 1 Diabetes (T1D). Previous studies suggested a role of CD5 expressing T and B cells including rare unconventional lymphocytes with combined T- and B-cell features (DE cells). We performed algorithm-supported multi-parameter flow cytometry and quantitative PCR to investigate immune cell subsets and DE cells in children with T1D (n=20) and matched controls (n=20). Comparisons of conventional immune cells detected increased proportions of CD3+ T cells in T1D patients whereas CD19+ B cell proportions were comparable to controls. Self-organizing maps for flow cytometry analyses (FlowSOM) showed highly similar CD5 expressing B-cell subsets and no differences for DE cells were detected between the study groups by flow cytometry or specific quantitative PCR. Notably, differences in CD8 positive T cells were indicated by FlowSOM and similarity-based tSNE analyses. Study group comparison confirmed significantly reduced CD8+ T-cell proportions with moderate or low CD5 expression in T1D patients. Finally, In vitro experiments showed stable CD5 expression differences of CD8+ T cells after T-cell activation, cytokine stimulation and culture. We observed differences of T-cell co-receptor CD5 expression in T1D patients with potential relevance for immune regulation of CD8+ T-cell activation.

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