Survival of autoreactive T lymphocytes by microRNA-mediated regulation of apoptosis through TRAIL and Fas in type 1 diabetes

Type 1 diabetes mellitus (DM1) is associated with compromised (defective) immunologic tolerance to autoantigens and selective destruction of pancreatic B-cells by CD4+ (effector) and CD8 (cytotoxic) lymphocytes. The mechanisms of autotolerance involve CD4+CD25+high T-regulatory cells (Treg) whose suppressor activity depends on the expression of the FoxP3 gene. Aim. Detection of quantitative and functional alterations at the level of regulation of immunity in subjects at risk of DM1 and patients with different duration of DM1. Materials and methods. 116 patients (67 men and 49 women) with different duration of DM1. The risk group was comprised of 33 subjects (10 men and 23 women), control group included 16 subjects. In all cases, HLA genotyping was performed, autoantibodies to GDC, insulin and tyrosine phosphatase, islet cell antigens were determined, subpopulation composition of CD3+, CD4+, CD8+, CD38+, HLA DR+, CD25+, CD4+25+ lymphocytes and their functional activities (FoxP3 gene expression) studied, C-peptie and HbA1c levels measured. Results. A tendency toward a rise in Cd25+ and CD4+25+ T-lymphocytes and a decrease in FoxP3 expression was documented in the risk group compared with control (p0.05) but their functional activity was lower (p

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The primacy of CD8 T lymphocytes in type 1 diabetes and implications for therapies

Journal of Molecular Medicine ◽

10.1007/s00109-009-0516-6 ◽

2009 ◽

Vol 87 (12) ◽

pp. 1173-1178 ◽

Cited By ~ 21

Author(s):

Denise L. Faustman ◽

Miriam Davis

Keyword(s):

Type 1 Diabetes ◽

T Lymphocytes ◽

Cd8 T Lymphocytes

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Making the Most of Major Histocompatibility Complex Molecule Multimers: Applications in Type 1 Diabetes

Clinical and Developmental Immunology ◽

10.1155/2012/380289 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Greg S. Gojanovich ◽

Paul R. Hess

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Major Histocompatibility Complex ◽

T Cell ◽

T Lymphocytes ◽

T Cell Subsets ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Pancreatic Islets Of Langerhans

Classical major histocompatibility complex (MHC) class I and II molecules present peptides to cognate T-cell receptors on the surface of T lymphocytes. The specificity with which T cells recognize peptide-MHC (pMHC) complexes has allowed for the utilization of recombinant, multimeric pMHC ligands for the study of minute antigen-specific T-cell populations. In type 1 diabetes (T1D), CD8+ cytotoxic T lymphocytes, in conjunction with CD4+ T helper cells, destroy the insulin-producingβcells within the pancreatic islets of Langerhans. Due to the importance of T cells in the progression of T1D, the ability to monitor and therapeutically target diabetogenic clonotypes of T cells provides a critical tool that could result in the amelioration of the disease. By administering pMHC multimers coupled to fluorophores, nanoparticles, or toxic moieties, researchers have demonstrated the ability to enumerate, track, and delete diabetogenic T-cell clonotypes that are, at least in part, responsible for insulitis; some studies even delay or prevent diabetes onset in the murine model of T1D. This paper will provide a brief overview of pMHC multimer usage in defining the role T-cell subsets play in T1D etiology and the therapeutic potential of pMHC for antigen-specific identification and modulation of diabetogenic T cells.

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T Cell Recognition of Autoantigens in Human Type 1 Diabetes: Clinical Perspectives

Clinical and Developmental Immunology ◽

10.1155/2011/513210 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 42

Author(s):

Roberto Mallone ◽

Vedran Brezar ◽

Christian Boitard

Keyword(s):

Type 1 Diabetes ◽

T Cell ◽

T Lymphocytes ◽

Disease Process ◽

Immune Correlates ◽

Autoreactive T Cell ◽

Cell Assays ◽

History Of ◽

Functional Features

Type 1 diabetes (T1D) is an autoimmune disease driven by the activation of lymphocytes against pancreaticβ-cells. Amongβ-cell autoantigens, preproinsulin has been ascribed a key role in the T1D process. The successive steps that control the activation of autoreactive lymphocytes have been extensively studied in animal models of T1D, but remains ill defined in man. In man, T lymphocytes, especially CD8+T cells, are predominant within insulitis. Developing T-cell assays in diabetes autoimmunity is, thus, a major challenge. It is expected to help defining autoantigens and epitopes that drive the disease process, to pinpoint key functional features of epitope-specific T lymphocytes along the natural history of diabetes and to pave the way towards therapeutic strategies to induce immune tolerance toβ-cells. New T-cell technologies will allow defining autoreactive T-cell differentiation programs and characterizing autoimmune responses in comparison with physiologically appropriate immune responses. This may prove instrumental in the discovery of immune correlates of efficacy in clinical trials.

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Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes

Acta Diabetologica ◽

10.1007/s00592-021-01711-z ◽

2021 ◽

Author(s):

Yimei Shan ◽

Yinghong Kong ◽

Yan Zhou ◽

Jingjing Guo ◽

Qiyun Shi ◽

...

Keyword(s):

Type 1 Diabetes ◽

T Lymphocytes ◽

Effector Memory ◽

Programmed Death ◽

Programmed Death 1 ◽

Memory T Lymphocytes

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Common patterns of gene regulation associated with Cesarean section and the development of islet autoimmunity – indications of immune cell activation

10.1101/167676 ◽

2017 ◽

Author(s):

M. Laimighofer ◽

R. Lickert ◽

R. Fürst ◽

F. J. Theis ◽

C. Winkler ◽

...

Keyword(s):

Gene Expression ◽

Type 1 Diabetes ◽

T Lymphocytes ◽

Cesarean Section ◽

Cell Activation ◽

Immune Cell ◽

Islet Autoimmunity ◽

Nucleotide Synthesis ◽

Immune Cell Activation

AbstractBackgroundBirth by Cesarean section increases the risk of developing type 1 diabetes later in life; however, the underlying molecular mechanisms of this effect remain unclear. We aimed to elucidate common regulatory processes observed after Cesarean section and the development of islet autoimmunity, which precedes type 1 diabetes, by investigating the transcriptome of blood cells in the developing immune system.MethodsWe analyzed gene expression of peripheral blood mononuclear cells taken at several time points from children with increased familial and genetic risk for type 1 diabetes (n = 109). We investigated effects of Cesarean section on gene expression profiles of children in the first year of life using a generalized additive mixed model to account for the longitudinal data structure. To investigate the effect of islet autoimmunity, we compared gene expression differences between children after initiation of islet autoimmunity and age-matched children who did not develop islet autoantibodies. Finally, we compared both results to identify common regulatory patterns of Cesarean section and islet autoimmunity at the gene expression level.ResultsWe identified two differentially expressed pathways in children born by Cesarean section: the pentose phosphate pathway and pyrimidine metabolism, both involved in nucleotide synthesis and cell proliferation. Islet autoantibody analysis revealed multiple differentially expressed pathways generally involved in immune processes, including both of the above-mentioned nucleotide synthesis pathways. Comparison of global gene expression signatures showed that transcriptomic changes were systematically and significantly correlated between Cesarean section and islet autoimmunity. In addition, signatures of both Cesarean section and islet autoimmunity correlated with transcriptional changes observed during activation of isolated CD4+ T lymphocytes.ConclusionsWe identified coherent gene expression signatures for Cesarean section, an early risk factor for type 1 diabetes, and islet autoantibodies positivity, an obligatory stage of autoimmune response prior to the development of type 1 diabetes. Both transcriptional signatures were correlated with changes in gene expression during the activation of CD4+ T lymphocytes, reflecting common molecular changes in immune cell activation.

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