scholarly journals A Single L/D-Substitution at Q4 of the mInsA2-10 Epitope Prevents Type 1 Diabetes in Humanized NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Mengjun Zhang ◽  
Yuanqiang Wang ◽  
Xiangqian Li ◽  
Gang Meng ◽  
Xiaoling Chen ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Inflammatory Responses ◽  
Nod Mice ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Altered Peptide Ligands

Autoreactive CD8+ T cells play an indispensable key role in the destruction of pancreatic islet β-cells and the initiation of type 1 diabetes (T1D). Insulin is an essential β-cell autoantigen in T1D. An HLA-A*0201-restricted epitope of insulin A chain (mInsA2-10) is an immunodominant ligand for autoreactive CD8+ T cells in NOD.β2mnull.HHD mice. Altered peptide ligands (APLs) carrying amino acid substitutions at T cell receptor (TCR) contact positions within an epitope are potential to modulate autoimmune responses via triggering altered TCR signaling. Here, we used a molecular simulation strategy to guide the generation of APL candidates by substitution of L-amino acids with D-amino acids at potential TCR contact residues (positions 4 and 6) of mInsA2-10, named mInsA2-10DQ4 and mInsA2-10DC6, respectively. We found that administration of mInsA2-10DQ4, but not DC6, significantly suppressed the development of T1D in NOD.β2mnull.HHD mice. Mechanistically, treatment with mInsA2-10DQ4 not only notably eliminated mInsA2-10 autoreactive CD8+ T cell responses but also prevented the infiltration of CD4+ T and CD8+ T cells, as well as the inflammatory responses in the pancreas of NOD.β2mnull.HHD mice. This study provides a new strategy for the development of APL vaccines for T1D prevention.

scholarly journals Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type-1 diabetes

2020 ◽  
Author(s):  
Heejoo Kim ◽  
Jelena Perovanovic ◽  
Arvind Shakya ◽  
Zuolian Shen ◽  
Cody N. German ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Target Genes ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Cell Receptor ◽  
Glucose Levels ◽  
Transcriptional Coregulator

AbstractThe transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present, but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice, but diminished in monoclonal models specific to artificial or neoantigens. Rationally-designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels, and reduced T cell infiltration and proinflammatory cytokine expression in newly-diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.~40-word summary statement for the online JEM table of contents and alertsKim and colleagues show that OCA-B in T cells is essential for the generation of type-1 diabetes. OCA-B loss leaves the pancreatic lymph nodes largely undisturbed, but associates autoreactive CD4+ T cells in the pancreas with anergy while deleting potentially autoreactive CD8+ T cells.SummaryKim et al. show that loss or inhibition of OCA-B in T cells protects mice from type-1 diabetes.

scholarly journals Proinsulin-Reactive CD4 T Cells in the Islets of Type 1 Diabetes Organ Donors

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurie G. Landry ◽  
Amanda M. Anderson ◽  
Holger A. Russ ◽  
Liping Yu ◽  
Sally C. Kent ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cd4 T Cells ◽  
Pancreatic Beta Cells ◽  
Hot Spot ◽  
Cell Receptor ◽  
Organ Donors ◽  
Hla Dq

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.

scholarly journals Self-reactive human CD4 T cell clones form unusual immunological synapses

2012 ◽  
Vol 209 (2) ◽  
pp. 335-352 ◽  
Author(s):  
David A. Schubert ◽  
Susana Gordo ◽  
Joseph J. Sabatino ◽  
Santosh Vardhana ◽  
Etienne Gagnon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
T Cell Clones ◽  
Cell Clones ◽  
Immunological Synapses ◽  
High Degree ◽  
Self Antigen

Recognition of self–peptide-MHC (pMHC) complexes by CD4 T cells plays an important role in the pathogenesis of many autoimmune diseases. We analyzed formation of immunological synapses (IS) in self-reactive T cell clones from patients with multiple sclerosis and type 1 diabetes. All self-reactive T cells contained a large number of phosphorylated T cell receptor (TCR) microclusters, indicative of active TCR signaling. However, they showed little or no visible pMHC accumulation or transport of TCR–pMHC complexes into a central supramolecular activation cluster (cSMAC). In contrast, influenza-specific T cells accumulated large quantities of pMHC complexes in microclusters and a cSMAC, even when presented with 100-fold lower pMHC densities. The self-reactive T cells also maintained a high degree of motility, again in sharp contrast to virus-specific T cells. 2D affinity measurements of three of these self-reactive T cell clones demonstrated a normal off-rate but a slow on-rate of TCR binding to pMHC. These unusual IS features may facilitate escape from negative selection by self-reactive T cells encountering very small amounts of self-antigen in the thymus. However, these same features may enable acquisition of effector functions by self-reactive T cells encountering large amounts of self-antigen in the target organ of the autoimmune disease.

scholarly journals Reduction of T Cell Receptor Diversity in NOD Mice Prevents Development of Type 1 Diabetes but Not Sjögren’s Syndrome

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112467 ◽  
Author(s):  
Joanna Kern ◽  
Robert Drutel ◽  
Silvia Leanhart ◽  
Marek Bogacz ◽  
Rafal Pacholczyk
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Receptor ◽  
Sjögren's Syndrome ◽  
Nod Mice ◽  
Cell Receptor ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

scholarly journals Identification of Candidate Tolerogenic CD8+T Cell Epitopes for Therapy of Type 1 Diabetes in the NOD Mouse Model

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Cailin Yu ◽  
Jeremy C. Burns ◽  
William H. Robinson ◽  
Paul J. Utz ◽  
Peggy P. Ho ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Nod Mice ◽  
Cell Protein ◽  
T Cell Epitopes ◽  
Predictive Algorithms ◽  
Murine Homolog ◽  
Human Type 1 Diabetes

Type 1 diabetes is an autoimmune disease in which insulin-producing pancreatic isletβcells are the target of self-reactive B and T cells. T cells reactive with epitopes derived from insulin and/or IGRP are critical for the initiation and maintenance of disease, but T cells reactive with other islet antigens likely have an essential role in disease progression. We sought to identify candidate CD8+T cell epitopes that are pathogenic in type 1 diabetes. Proteins that elicit autoantibodies in human type 1 diabetes were analyzed by predictive algorithms for candidate epitopes. Using several different tolerizing regimes using synthetic peptides, two new predicted tolerogenic CD8+T cell epitopes were identified in the murine homolog of the major human islet autoantigen zinc transporter ZnT8 (aa 158–166 and 282–290) and one in a non-βcell protein, dopamineβ-hydroxylase (aa 233–241). Tolerizing vaccination of NOD mice with a cDNA plasmid expressing full-length proinsulin prevented diabetes, whereas plasmids encoding ZnT8 and DβH did not. However, tolerizing vaccination of NOD mice with the proinsulin plasmid in combination with plasmids expressing ZnT8 and DβH decreased insulitis and enhanced prevention of disease compared to vaccination with the plasmid encoding proinsulin alone.

scholarly journals Differentiating MHC-dependent and -independent mechanisms of lymph node stromal cell regulation of proinsulin-specific CD8+ T-cells in type 1 diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Terri C. Thayer ◽  
Joanne Davies ◽  
James A. Pearson ◽  
Stephanie J. Hanna ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Lymph Node ◽  
T Cell ◽  
Cell Receptor ◽  
Peripheral Tolerance ◽  
Beta Cell Destruction ◽  
Nonobese Diabetic ◽  
Autoreactive Cells

Lymph node stromal cells (LNSC) are essential for providing and maintaining peripheral self-tolerance of potentially autoreactive cells. In type 1 diabetes, proinsulin-specific CD8<sup>+</sup>T-cells, escaping central and peripheral tolerance, contribute to beta-cell destruction. Using G9Cα<sup>-/-</sup>CD8<sup>+</sup>T-cells specific for proinsulin, we studied the mechanisms by which LNSC regulate low-avidity autoreactive cells in the nonobese diabetic (NOD) mouse model of type 1 diabetes. Whereas MHC-matched NOD-LNSC significantly reduced G9Cα<sup>-/-</sup>CD8<sup>+</sup>T-cell cytotoxicity and DC-induced proliferation, they failed to sufficiently regulate T-cells stimulated by anti-CD3/CD28. In contrast, non-MHC matched, control C57BL/6 mouse LNSC suppressed T-cell receptor engagement by anti-CD3/CD28 via MHC-independent mechanisms. This C57BL/6-LNSC suppression was maintained even after removal of the LNSC, demonstrating a direct effect of LNSC on T-cells, modifying antigen sensitivity and effector function. Thus, our results suggest that a loss of NOD-LNSC MHC-independent suppressive mechanisms may contribute to diabetes development.

scholarly journals IL-10 Deficiency Accelerates Type 1 Diabetes Development via Modulation of Innate and Adaptive Immune Cells and Gut Microbiota in BDC2.5 NOD Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Huang ◽  
Qiyuan Tan ◽  
Ningwen Tai ◽  
James Alexander Pearson ◽  
Yangyang Li ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Gut Microbiota ◽  
Spontaneous Diabetes ◽  
Nod Mice ◽  
Treg Cells ◽  
Diabetes Development

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells. BDC2.5 T cells in BDC2.5 CD4+ T cell receptor transgenic Non-Obese Diabetic (NOD) mice (BDC2.5+ NOD mice) can abruptly invade the pancreatic islets resulting in severe insulitis that progresses rapidly but rarely leads to spontaneous diabetes. This prevention of diabetes is mediated by T regulatory (Treg) cells in these mice. In this study, we investigated the role of interleukin 10 (IL-10) in the inhibition of diabetes in BDC2.5+ NOD mice by generating Il-10-deficient BDC2.5+ NOD mice (BDC2.5+Il-10-/- NOD mice). Our results showed that BDC2.5+Il-10-/- NOD mice displayed robust and accelerated diabetes development. Il-10 deficiency in BDC2.5+ NOD mice promoted the generation of neutrophils in the bone marrow and increased the proportions of neutrophils in the periphery (blood, spleen, and islets), accompanied by altered intestinal immunity and gut microbiota composition. In vitro studies showed that the gut microbiota from BDC2.5+Il-10-/- NOD mice can expand neutrophil populations. Moreover, in vivo studies demonstrated that the depletion of endogenous gut microbiota by antibiotic treatment decreased the proportion of neutrophils. Although Il-10 deficiency in BDC2.5+ NOD mice had no obvious effects on the proportion and function of Treg cells, it affected the immune response and activation of CD4+ T cells. Moreover, the pathogenicity of CD4+ T cells was much increased, and this significantly accelerated the development of diabetes when these CD4+ T cells were transferred into immune-deficient NOD mice. Our study provides novel insights into the role of IL-10 in the modulation of neutrophils and CD4+ T cells in BDC2.5+ NOD mice, and suggests important crosstalk between gut microbiota and neutrophils in type 1 diabetes development.

scholarly journals Using the T Cell Receptor as a Biomarker in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Maki Nakayama ◽  
Aaron W. Michels
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Current Knowledge ◽  
Autoimmune Diabetes ◽  
Cell Activity ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Unique Markers

T cell receptors (TCRs) are unique markers that define antigen specificity for a given T cell. With the evolution of sequencing and computational analysis technologies, TCRs are now prime candidates for the development of next-generation non-cell based T cell biomarkers, which provide a surrogate measure to assess the presence of antigen-specific T cells. Type 1 diabetes (T1D), the immune-mediated form of diabetes, is a prototypical organ specific autoimmune disease in which T cells play a pivotal role in targeting pancreatic insulin-producing beta cells. While the disease is now predictable by measuring autoantibodies in the peripheral blood directed to beta cell proteins, there is an urgent need to develop T cell markers that recapitulate T cell activity in the pancreas and can be a measure of disease activity. This review focuses on the potential and challenges of developing TCR biomarkers for T1D. We summarize current knowledge about TCR repertoires and clonotypes specific for T1D and discuss challenges that are unique for autoimmune diabetes. Ultimately, the integration of large TCR datasets produced from individuals with and without T1D along with computational ‘big data’ analysis will facilitate the development of TCRs as potentially powerful biomarkers in the development of T1D.

scholarly journals How C-terminal additions to insulin B-chain fragments create superagonists for T cells in mouse and human type 1 diabetes

2019 ◽  
Vol 4 (34) ◽  
pp. eaav7517 ◽  
Author(s):  
Yang Wang ◽  
Tomasz Sosinowski ◽  
Andrey Novikov ◽  
Frances Crawford ◽  
Janice White ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Proper Position ◽  
Peptide Epitopes ◽  
Human Type 1 Diabetes

In type 1 diabetes (T1D), proinsulin is a major autoantigen and the insulin B:9-23 peptide contains epitopes for CD4+ T cells in both mice and humans. This peptide requires carboxyl-terminal mutations for uniform binding in the proper position within the mouse IAg7 or human DQ8 major histocompatibility complex (MHC) class II (MHCII) peptide grooves and for strong CD4+ T cell stimulation. Here, we present crystal structures showing how these mutations control CD4+ T cell receptor (TCR) binding to these MHCII-peptide complexes. Our data reveal stricking similarities between mouse and human CD4+ TCRs in their interactions with these ligands. We also show how fusions between fragments of B:9-23 and of proinsulin C-peptide create chimeric peptides with activities as strong or stronger than the mutated insulin peptides. We propose transpeptidation in the lysosome as a mechanism that could accomplish these fusions in vivo, similar to the creation of fused peptide epitopes for MHCI presentation shown to occur by transpeptidation in the proteasome. Were this mechanism limited to the pancreas and absent in the thymus, it could provide an explanation for how diabetogenic T cells escape negative selection during development but find their modified target antigens in the pancreas to cause T1D.

scholarly journals The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes

2021 ◽  
Vol 11 ◽  
Author(s):  
Matthew Clark ◽  
Charles J. Kroger ◽  
Qi Ke ◽  
Roland M. Tisch
Keyword(s):  
Type 1 Diabetes ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Response ◽  
Peripheral Tolerance ◽  
Tcr Signaling ◽  
Signaling Events ◽  
Cell Gene Expression

T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.

Sign in / Sign up

Export Citation Format

Share Document