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Characterization and effective expansion of CD4-CD8- TCRab+ T cells from individuals living with type 1 diabetes

ABSTRACT: CD4-CD8- TCRab+ (double-negative [DN]) T cells represent a rare T cell population that promotes immunological tolerance through various cytotoxic mechanisms. In mice, autologous transfer of DN T cells has shown protective effects against autoimmune diabetes and graft-versus-host disease. Here, we characterized humanDNT cells from people living with type 1 diabetes (PWT1D) and healthy controls. We found that while DN T cells and CD8+ T cells share many similarities, DN T cells are a unique T cell population, both at the transcriptomic and protein levels. We also show that by using various cytokine combinations, human DN T cells can be expanded in vitro up to 1,000- fold (mean >250-fold) and remain functional post-expansion. In addition, we report that DN T cells from PWT1D display a phenotype comparable to that of healthy controls, efficiently expand, and are highly functional. As DN T cells are immunoregulatory and can prevent T1D in various mouse models, these observations suggest that autologous DN T cells may be amenable to therapy for the prevention or treatment of T1D.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285617 | GEO | 2025/01/05

REPOSITORIES: GEO

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Characterization and effective expansion of CD4-CD8- TCRab+ T cells from individuals living with type 1 diabetes

Project description:Characterization and effective expansion of CD4-CD8- TCRab+ T cells from individuals living with type 1 diabetes

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2022-10-14 | PXD031966 | Pride

Global expression profiling of peripheral Qa-1 class Ib-restricted CD8aa+TCRab+ regulatory T Cells reveals innate-like features: implications for immune regulatory repertoire

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Project description:Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) was the first therapeutic approaches that can improve beta cell function in type 1 diabetic (T1D) patients. This study was designed to investigate the potential mechanisms involved.We applied AHST to nine T1D patients diagnosed within six months and analyzed the acute response in peripheral blood genomic expression profiling at the six-month follow-up. Peripheral blood mononuclear of newly diagnosed type1 diabetes patients at diagnosis and at six months post-transplantation by autologous peripheral stem cell were purified by LymphoprepTm gradient purification according to the manufacturer's instructions (Axis-Shield PoC AS, Oslo, Norway) for futher microarray analysis.

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Ubiquitin Thioesterase OTUB2 is An Endoplasmic Reticulum Stress-associated β Cell Autoantigen Targeted by CD8+ T cells in Type 1 Diabetes

Project description:Autoreactive CD8+ T cell plays a key role in the pathogenesis of Type 1 diabetes (T1D), but the antigen spectrum that activate autoreactive CD8+ T cells is still not completely clear. Endoplasmic reticulum stress（ERS）has been implicated in the generation of β cell autoantigens and the enhanced immune visibility of β cells to autoreactive T cells. Here, we in-depth analyzed the major histocompatibility complex class I (MHC-I) associated immunopeptidome (MIP) of islets β cell under steady-state and ERS-state, and found couples of peptides exclusively present in the MIP of β cell line under ERS state. Among them, peptide OTUB258-66 derived from ubiquitin thioesterase OTUB2 showed immunodominance in NOD mice, and autoreactive CD8+ T cells targeting OTUB258-66 were diabetogenic in NOD mice. High glucose intake upregulated the expression of OTUB2 in the pancreas and amplified the OTUB258-66-specific CD8+ T cell response in NOD mice. Repeated administration with OTUB258-66 significantly reduced the incidence of T1D in NOD mice. This study not only provides an explanation for the role of ERS induced by environmental factors such as high glucose intake in promoting β cell autoimmune injury, but also provides a novel ERS-associated β cell autoantigens for developing specific immune intervention in prevention and treatment of T1D.

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Transcription Regulatory Networks of CD4 CD8 and CD14 cells in Patients of Type I Mellitus Diabetes

Project description:Insulin-dependent diabetes mellitus (T1D) is an organ-specific auto-immune disease caused by the selective destruction of the pancreatic beta cells by inflammatory cells, especially auto-reactive CD8+ T lymphocytes. In this study we evaluated the differential large scale gene expression profiling using cDNA microarrays of T (CD4+ and CD8+) and monocyte (CD14+) cells. In addition, considering that HLA class II profile may influence the expression of these molecules on the surface of peripheral blood cells, and considering that the mechanisms by which HLA class II susceptibility alleles drive the auto-immune response have not been elucidated, we intend to further stratify T1D patients according to the HLA class II profile. 20 pre-pubertal recently diagnosed T1D patients were selected, HLA-DRB1/DQB1 allele typing and separated in two groups. The group 1(G1) had patients with susceptibility alleles and group 2 (G2) with at least one protection allele. To established relationships between genes, the GeneNetwork 1.2 algorithm was used, 6 networks were obtained, TCD4+ G1 patients X controls, TCD4+ G2 patients X controls, and same situation to TCD8+ and CD14+.

2011-06-15 | E-MEXP-3223 | biostudies-arrayexpress

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Project description:Type 1 diabetes is an autoimmune disease in which insulin-secreting β cells of the pancreatic islets are selectively destroyed. CD8 T cells are regarded as critical players in mediating β cell destruction and as a result, considerable effort has been expended to define CD8 T cell behaviour in this disease. The overarching aim of the experiment is to characterize a recently identified autoreactive CD57-positive CD8 T cell subset which is associated with loss of function of islet beta cells in type 1 diabetes, to compare the phenotype of the CD57-positive effector memory CD8 T cells versus the CD57-negative compartment, and provide an insight into the function of these cells in the disease process. To that aim, HLA-A*24 positive patients with T1D -within 2 years of diagnosis- were asked to provide a blood, and following consent, and PBMC were isolated. CD57-positive and CD57-negative CD8 T cell populations were sorted by FACS, and finally, RNA was extracted. Amplified cDNA was obtained and used for the library preparation.

2018-08-03 | E-MTAB-6727 | biostudies-arrayexpress

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Project description:Gene expression analyses of fibroblasts obtained from healthy controls, Medalist -C patients and Medalist +C patients. Type 1diabetes (T1D) is associated with late complications, mechanisms underscoring which are poorly understood. We report the derivation of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50years) with severe (designated Medalist +C) or absent to mild complications (designated Medalist -C). Disease modeling of iPSCs revealed impairment in growth, reprogramming and differentiation in Medalist +C. Further investigations using genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist –C. In silico analyses revealed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs showed enhanced susceptibility to genotoxic stress that worsened upon miR200 over-expression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage response. In summary, we report miR200 regulated DNA damage checkpoint pathway as a potential target for therapeutic intervention for treating complications of diabetes. Clinical Characteristics of 50 year Medalist Type 1 Diabetes (T1D) patients Medalist –C: 0/6 with CVD, 5/6 have DN Class 0-IIA, and 6/6 have no to mild NPDR. Medalist +C: 6/6 with CVD, 5/6 have DN Class IIB or IV, and 4/6 have PDR. CVD: cardiovascular disease; DN class: diabetic nephropathy class, PDR: proliferative diabetic retinopathy; NPDR: non proliferative diabetic retinopathy

2015-08-15 | GSE70752 | GEO

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