scholarly journals Proinsulin-specific T regulatory cells may control immune responses in type 1 diabetes: implications for adoptive therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000873 ◽  
Author(s):  
Mateusz Gliwiński ◽  
Dorota Iwaszkiewicz-Grześ ◽  
Anna Wołoszyn-Durkiewicz ◽  
Monika Tarnowska ◽  
Magdalena Żalińska ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Immune Responses ◽  
T Regulatory Cells ◽  
Cell Receptor ◽  
Regulatory Cells ◽  
Antigen Specificity ◽  
Adoptive Therapy

ObjectiveHere we looked for possible mechanisms regulating the progression of type 1 diabetes mellitus (T1DM). In this disease, autoaggressive T cells (T conventional cells, Tconvs) not properly controlled by T regulatory cells (Tregs) destroy pancreatic islets.Research design and methodsWe compared the T-cell compartment of patients with newly diagnosed T1DM (NDT1DM) with long-duration T1DM (LDT1DM) ones. The third group consisted of patients with LDT1DM treated previously with polyclonal Tregs (LDT1DM with Tregs). We have also looked if the differences might be dependent on the antigen specificity of Tregs expanded for clinical use and autologous sentinel Tconvs.ResultsPatients with LDT1DM were characterized by T-cell immunosenescence-like changes and expansion of similar vβ/T-cell receptor (TCR) clones in Tconvs and Tregs. The treatment with Tregs was associated with some inhibition of these effects. Patients with LDT1DM possessed an increased percentage of various proinsulin-specific T cells but not GAD65-specific ones. The percentages of all antigen-specific subsets were higher in the expansion cultures than in the peripheral blood. The proliferation was more intense in proinsulin-specific Tconvs than in specific Tregs but the levels of some proinsulin-specific Tregs were exceptionally high at baseline and remained higher in the expanded clinical product than the levels of respective Tconvs in sentinel cultures.ConclusionsT1DM is associated with immunosenescence-like changes and reduced diversity of T-cell clones. Preferential expansion of the same TCR families in both Tconvs and Tregs suggests a common trigger/autoantigen responsible. Interestingly, the therapy with polyclonal Tregs was associated with some inhibition of these effects. Proinsulin-specific Tregs appeared to be dominant in the immune responses in patients with T1DM and probably associated with better control over respective autoimmune Tconvs.Trial registration numberEudraCT 2014-004319-35.

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 In Vivo Selection of T-Cell Receptor Junctional Region Sequences by HLA-A2 Human T-Cell Lymphotropic Virus Type 1 Tax11-19 Peptide Complexes

2001 ◽  
Vol 75 (2) ◽  
pp. 1065-1071 ◽  
Author(s):  
Mineki Saito ◽  
Graham P. Taylor ◽  
Akiko Saito ◽  
Yoshitaka Furukawa ◽  
Koichiro Usuku ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Virus Type ◽  
Cell Receptor ◽  
Antigen Specificity ◽  
Human T Cell ◽  
Cdr3 Region

ABSTRACT Using HLA-peptide tetrameric complexes, we isolated human T-cell lymphotrophic virus type 1 Tax peptide-specific CD8+ T cells ex vivo. Antigen-specific amino acid motifs were identified in the T-cell receptor Vβ CDR3 region of clonally expanded CD8+ T cells. This result directly confirms the importance of the CDR3 region in determining the antigen specificity in vivo.

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 BDC12-4.1 T-Cell Receptor Transgenic Insulin-Specific CD4 T Cells Are Resistant to In Vitro Differentiation into Functional Foxp3+ T Regulatory Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112242 ◽  
Author(s):  
Ghanashyam Sarikonda ◽  
Georgia Fousteri ◽  
Sowbarnika Sachithanantham ◽  
Jacqueline F. Miller ◽  
Amy Dave ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Cell Receptor ◽  
Regulatory Cells ◽  
In Vitro Differentiation

scholarly journals Heterogeneity of T Cells in Atherosclerosis Defined by Single-Cell RNA-Sequencing and Cytometry by Time of Flight

2020 ◽  
Author(s):  
Holger Winkels ◽  
Dennis Wolf
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
T Regulatory Cells ◽  
Foam Cell ◽  
Regulatory Cells ◽  
T Helper ◽  
Antigen Specificity ◽  
Single Cell Rna Sequencing

The infiltration and accumulation of pro- and anti-inflammatory leukocytes within the intimal layer of the arterial wall is a hallmark of developing and progressing atherosclerosis. While traditionally perceived as macrophage- and foam cell-dominated disease, it is now established that atherosclerosis is a partial autoimmune disease that involves the recognition of peptides from ApoB (apolipoprotein B), the core protein of LDL (low-density lipoprotein) cholesterol particles, by CD4 + T-helper cells and autoantibodies against LDL and ApoB. Autoimmunity in the atherosclerotic plaque has long been understood as a pathogenic T-helper type-1 driven response with proinflammatory cytokine secretion. Recent developments in high-parametric cell immunophenotyping by mass cytometry, single-cell RNA-sequencing, and in tools exploring antigen-specificity have established the existence of several unforeseen layers of T cell diversity with mixed T H 1 and T regulatory cells transcriptional programs and unpredicted fates. These findings suggest that pathogenic ApoB-reactive T cells evolve from atheroprotective and immunosuppressive CD4 + T regulatory cells that lose their protective properties over time. Here, we discuss T cell heterogeneity in atherosclerosis with a focus on plasticity, antigen-specificity, exhaustion, maturation, tissue residency, and its potential use in clinical prediction.

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 Application of IgG-Derived Natural Treg Epitopes (IgG Tregitopes) to Antigen-Specific Tolerance Induction in a Murine Model of Type 1 Diabetes

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Leslie P. Cousens ◽  
Yan Su ◽  
Elizabeth McClaine ◽  
Xin Li ◽  
Frances Terry ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Immune Responses ◽  
Murine Model ◽  
Regulatory T Cell ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
The Impact

HLA class II-restricted regulatory T cell (Treg) epitopes in IgG (also called “Tregitopes”) have been reported to suppress immune responses to coadministered antigens by stimulating the expansion of natural Tregs (nTregs). Here we evaluate their impact on human immune responses to islet cell antigensex vivoand on the modulation of type 1 diabetes (T1D) in a murine modelin vivo. Co-administration of Tregitopes and T1D antigens delayed development of hyperglycemia and reduced the incidence of diabetes in NOD mice. Suppression of diabetes could be observed even following onset of disease. To measure the impact of Tregitope treatment on T cell responses, we evaluated the effect of Tregitope treatment in DO11.10 mice. Upregulation of FoxP3 in KJ1-26-stained OVA-specific CD4+T cells was observed following treatment of DO11.10 mice with Tregitopes, along with reductions in anti-OVA Ig and T effector responses. Inex vivostudies of human T cells, peripheral blood mononuclear cells’ (PBMC) responses to GAD65 epitopes in the presence and absence of Tregitope were variable. Suppression of immune responses to GAD65 epitopesex vivoby Tregitope appeared to be more effective in assays using PBMC from a newly diagnosed diabetic subject than for other more established diabetic subjects, and correlation of the degree of suppression with predicted HLA restriction of the Tregitopes was confirmed. Implementation of these defined regulatory T cell epitopes for therapy of T1D and other autoimmune diseases may lead to a paradigm shift in disease management.

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 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.

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