scholarly journals Activated but functionally impaired memory Tregs are expanded in slow progressors to type 1 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Joanne Boldison ◽  
Anna E. Long ◽  
Rachel J. Aitken ◽  
Isabel V. Wilson ◽  
Clare Megson ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Unsupervised Clustering ◽  
Autoimmune Response ◽  
Peripheral Blood Mononuclear ◽  
Slow Progressors ◽  
Healthy Donors

Abstract Aims/hypothesis Slow progressors to type 1 diabetes are individuals positive for multiple pancreatic islet autoantibodies who have remained diabetes-free for at least 10 years; regulation of the autoimmune response is understudied in this group. Here, we profile CD4+ regulatory T cells (Tregs) in a small but well-characterised cohort of extreme slow progressors with a median age 43 (range 31–72 years), followed up for 18–32 years. Methods Peripheral blood samples were obtained from slow progressors (n = 8), age- and sex-matched to healthy donors. One participant in this study was identified with a raised HbA1c at the time of assessment and subsequently diagnosed with diabetes; this donor was individually evaluated in the analysis of the data. Peripheral blood mononuclear cells (PBMCs) were isolated, and to assess frequency, phenotype and function of Tregs in donors, multi-parameter flow cytometry and T cell suppression assays were performed. Unsupervised clustering analysis, using FlowSOM and CITRUS (cluster identification, characterization, and regression), was used to evaluate Treg phenotypes. Results Unsupervised clustering on memory CD4+ T cells from slow progressors showed an increased frequency of activated memory CD4+ Tregs, associated with increased expression of glucocorticoid-induced TNFR-related protein (GITR), compared with matched healthy donors. One participant with a raised HbA1c at the time of assessment had a different Treg profile compared with both slow progressors and matched controls. Functional assays demonstrated that Treg-mediated suppression of CD4+ effector T cells from slow progressors was significantly impaired, compared with healthy donors. However, effector CD4+ T cells from slow progressors were more responsive to Treg suppression compared with healthy donors, demonstrated by increased suppression of CD25 and CD134 expression on effector CD4+ T cells. Conclusions/interpretations We conclude that activated memory CD4+ Tregs from slow progressors are expanded and enriched for GITR expression, highlighting the need for further study of Treg heterogeneity in individuals at risk of developing type 1 diabetes. Graphical abstract

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 Type 1 diabetes alters lipid handling and metabolism in human fibroblasts and peripheral blood mononuclear cells

PLoS ONE ◽  
2017 ◽  
Vol 12 (12) ◽  
pp. e0188474 ◽  
Author(s):  
Albert R. Jones IV ◽  
Emily L. Coleman ◽  
Nicholas R. Husni ◽  
Jude T. Deeney ◽  
Forum Raval ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Fibroblasts ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Human Immunodeficiency Virus Type 1 DNA Sequences Genetically Damaged by Hypermutation Are Often Abundant in Patient Peripheral Blood Mononuclear Cells and May Be Generated during Near-Simultaneous Infection and Activation of CD4+ T Cells

2001 ◽  
Vol 75 (17) ◽  
pp. 7973-7986 ◽  
Author(s):  
Mario Janini ◽  
Melissa Rogers ◽  
Deborah R. Birx ◽  
Francine E. McCutchan
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Blood Mononuclear Cells ◽  
Hiv 1

ABSTRACT G-to-A hypermutation has been sporadically observed in human immunodeficiency virus type 1 (HIV-1) proviral sequences from patient peripheral blood mononuclear cells (PBMC) and virus cultures but has not been systematically evaluated. PCR primers matched to normal and hypermutated sequences were used in conjunction with an agarose gel electrophoresis system incorporating an AT-binding dye to visualize, separate, clone, and sequence hypermutated and normal sequences in the 297-bp HIV-1 protease gene amplified from patient PBMC. Among 53 patients, including individuals infected with subtypes A through D and at different clinical stages, at least 43% of patients harbored abundant hypermutated, along with normal, protease genes. In 70 hypermutated sequences, saturation of G residues in the GA or GG dinucleotide context ranged from 20 to 94%. Levels of other mutants were not elevated, and G-to-A replacement was entirely restricted to GA or GG, and not GC or GT, dinucleotides. Sixty-nine of 70 hypermutated and 3 of 149 normal sequences had in-frame stop codons. To investigate the conditions under which hypermutation occurs in cell cultures, purified CD4+ T cells from normal donors were infected with cloned NL4-3 virus stocks at various times before and after phytohemagglutinin (PHA) activation. Hypermutation was pronounced when HIV-1 infection occurred simultaneously with, or a few hours after, PHA activation, but after 12 h or more after PHA activation, most HIV-1 sequences were normal. Hypermutated sequences generated in culture corresponded exactly in all parameters to those obtained from patient PBMC. Near-simultaneous activation and infection of CD4+ T cells may represent a window of susceptibility where the informational content of HIV-1 sequences is lost due to hypermutation.

Low bone mineral density in patients with type 1 diabetes: association with reduced expression ofIGF1,IGF1RandTGF B 1in peripheral blood mononuclear cells

2016 ◽  
Vol 32 (6) ◽  
pp. 589-595 ◽  
Author(s):  
Karla Simone Costa de Souza ◽  
Marcela Abbott Galvão Ururahy ◽  
Yonara Monique da Costa Oliveira ◽  
Melina Bezerra Loureiro ◽  
Heglayne Pereira Vital da Silva ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Type 1 Diabetes ◽  
Bone Mineral ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Mineral Density ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Circulating and cell-bound antibodies increase coxsackievirus B4-induced production of IFN-α by peripheral blood mononuclear cells from patients with type 1 diabetes

2002 ◽  
Vol 83 (9) ◽  
pp. 2169-2176 ◽  
Author(s):  
Didier Hober ◽  
Wassim Chehadeh ◽  
Jacques Weill ◽  
Christine Hober ◽  
Marie-Christine Vantyghem ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Healthy Subjects ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Coxsackievirus B4 ◽  
Blood Mononuclear Cells

Increased levels of IFN-α have been found in patients with type 1 diabetes who have detectable levels of coxsackievirus B4 (CVB4) RNA in their blood. The IFN-α-inducing activity of CVB4 in vitro is weak but can be enhanced by human IgGs. Therefore, it was investigated in vitro whether a preferential IFN-α response of peripheral blood mononuclear cells (PBMCs) to CVB4 exists in patients with type 1 diabetes (n=56) compared with healthy subjects (n=20) and whether antibodies play a role. In patients, the levels of IFN-α obtained after stimulation by PBMCs with CVB4 were higher (P=0·008), an individual IFN-α response by PBMCs to CVB4 was more frequent (P=0·0004) and increased levels of IFN-α were observed in CVB4-infected whole blood cultures. The IFN-α-inducing activity of patients plasma and IgGs mixed with CVB4 and then added to PBMCs was high in comparison with healthy subjects (P<0·001) and was inhibited by preincubating the cells with anti-FcγRII, anti-FcγRIII and anti-CAR (coxsackievirus and adenovirus receptor) antibodies. The strong IFN-α responsiveness of PBMCs to CVB4 suggested that IgGs bound to the cell surface might play a role. A short 56 °C incubation of PBMCs from patients responsive to CVB4 generated supernatants, which, when added to cells, exhibited IFN-α-enhancing activity in combination with CVB4, whereas those of controls did not. Specific antibodies for FcγRI, FcγRII and CAR inhibited this activity. These studies demonstrate that CVB4, through interactions with circulating and/or cell-bound IgGs, can strongly induce the production of IFN-α by PBMCs from patients with type 1 diabetes.

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