Abstracts Archive

Background: Mesenchymal stromal cells (MSCs) are inherently immunomodulatory, in particular when activated. We tested whether activated MSCs qualify for the induction of islet antigen specific immune regulation. Methods: Bone marrow derived human MSCs were activated by interferon-g (IFNg) and analyz...

CD8+T cells survey the repertoire of antigenic peptides on beta cells presented in the context of HLA-I. During insulitis, metabolic or inflammatory stress in the vicinity of beta cells induces local enzymatic activities and promotes the generation of post-translationally modified (PTM) neoantigens ...

Homeostatic antigen presentation by hepatic antigen presenting cells (HAPCs) results in tolerogenic, and not effector, T cell education. For this reason, strategies that target antigens to HAPCs have the potential to induce antigen-specific immunological tolerance. Here, we show that antigens modifi...

Alleles at the HLA-DRB1, DQA1 and DQB1 loci confer the greatest genetic predisposition to type 1 diabetes (T1D). However, a compelling rationale for this link, and especially for HLA-DQ-mediated disease predisposition, remains obscure. Given the antigen presenting function of HLA class II and the ro...

Dimethyl sulfoxide (DMSO) is a polar organic solvent ubiquitously used in a wide range of biological applications and research areas. DMSO is toxic for cells at high concentrations, but its toxicity at low concentrations is insufficiently investigated. DMSO is routinely used as a cryoprotectant for ...

  BACKGROUND: Analysis of autoantigen-specific CD4+ T cells is key for the understanding of T1D pathogenesis. To meet the dual challenge of understanding the frequency of such cells in different cellular compartments and their antigen experience, we developed an approach that combines T cell recept...

Background Recently, we reported a novel β cell population with compromised β cell signatures that are able to survive and proliferate as a result of autoimmunity during the disease progression in NOD mice. The intrinsic vulnerability of β cells to ER stress and oxidative stress-induced dysf...

In mice, immune responses to antigen administered in the absence of adjuvant are typically tolerogenic through the induction of regulatory T cells (Treg) and the deletion/inactivation of conventional T cells (Tconv). Nevertheless, antigen-specific immunotherapy (ASI) approaches in autoimmune and al...

Background Insulin and chromogranin A (ChgA) are autoantigens for CD4 T cells in the NOD mouse model of type-1 diabetes. Natural peptides from Insulin (B:9-23) and chromogranin A (WE14) are both weak antigens for diabetogenic CD4 T cells. Studies from our lab show that these peptides can be converte...

  Hmgb1 is an evolutionarily conserved chromosomal protein. It was recently re-discovered to be a potent innate alarmin implicated in both innate and adaptive immune response when it is present extracellularly. Hmgb1 can be either passively released by damaged cells or actively secreted by activate...

Background: Most pathogenic T cells in NOD mice recognize an insulin B:9-23 derived peptide bound to the I-Ag7 MHC class II molecule in the weak affinity register 3 (R3). The IAg7/B:9-23(R3) complex contains two epitopes based on peptides with or without the native glutamate at position B21 or the c...

Background: T-cell receptors (TCRs) used by T cells in the islets and antigens targeted by such T-cells may be utilized for T-cell biomarkers and therapeutic purposes for type 1 diabetes (T1D). Thus, we aimed to determine islet-specific TCR repertoires and their antigen specificity. Methods: We isol...

Background: In previous studies of NOD mice, anti-CD3 plus oral delivery of live Lactococcus lactis genetically modified to secrete the autoantigen proinsulin (PINS) with the tolerogenic cytokine IL-10 (L. lactis?PINS/IL-10) reversed T1D. We hypothesized that a short course of low-...

Background - The antigens and epitopes recognized by CD4+ T cells in people with type 1 diabetes (T1D) remain poorly defined. We, and others, have found that several epitopes derived from C-peptide are recognized by human islet-infiltrating CD4+ T cells implicating C-peptide as an autoantigen i...

      Introduction. CD8+ T-cell-mediated autoimmune β-cell destruction occurs in T1D. Such destruction may be favored by an increased β-cell vulnerability through the presentation of neo-epitopes more prone to escape tolerance. In this respect, post-translationally modified target peptides have...

Background: Two transgenic NOD mouse models, the NOD-PerIg and the 116C-NOD, were generated and characterized to better understand the role of B cells in the development of T1D. The NOD-PerIg model expresses an immunoglobulin of naturally occurring islet-infiltrating B-lymphocyte (IIBLs) in NOD mice...

Background The CRISPR-Cas9 system has been developed into a phenotype screening strategy. Using lentiviral delivery of a large collection of gRNAs, thousands of genes can be targeted for Cas9-mediated disruption in mammalian cells. Growing evidence supports ER stress as a target to prevent the initi...

Islet antigen reactive memory CD4 (IARM-CD4) T cells contribute to the development of type 1 diabetes (T1D), and are detected in peripheral blood before and after diagnosis. We used a CD154 activation assay in conjunction with single cell RNAseq of IARM-CD4 T cells to identify novel characteristics ...

Background Inflammatory cytokines, particularly the interferons, have been implicated in the pathogenesis of type 1 diabetes (T1D). Interferon-stimulated genes, including those that encode MHC proteins, are pathological hallmarks of the pancreatic islet during the development of T1D in both humans a...

Human CD4 T cells recognize the c-terminally modified insulin B:9-23 peptide in the same fashion as mouse diabetogenic T cells Yang Wang1,2, Tomasz Sosinowski3, Andrey Novikov1, Frances Crawford4, Howard W. Davidson2,3, Laurent Gapin2, John Kappler2,4, and Shaodong Dai1,2 1Department of Pharmaceutic...

It is important to identify defects in whole pancreas of subjects who develop type 1 diabetes (T1D) that distinguish them from genetically susceptible individuals who remain disease-free. It is unclear which biological processes are impaired and when this first occurs. Pancreas biopsies from diabet...

Multiple studies suggest that the strength of the T cell receptor (TCR) signal leading to regulatory T cell (Treg) development and function is unique and distinct from effector T cells (Teffs). However, functional implications of a unique Treg TCR repertoire in autoimmune diabetes are largely unknow...

B cells are key contributors to the pathology of T1D, demonstrated by numerous studies in both mouse and man. However, B cell subsets, which include IL-10 producing Bregs, can regulate disease development. In the NOD mouse model, although female mice have higher incidence of spontaneous diabetes, ov...

Background We reported that T cells, isolated directly from the islets of donors with T1D, recognized a broad repertoire of islet-associated targets, including post-translationally modified epitopes. From a study examining islet-associated proteins for potential sites of deamidation by transglutamin...

  Immune-based therapies for T1D need to focus on restoring self-tolerance without the need for chronic immunosuppression. CD4+Foxp3+ regulatory T-cells (Tregs) maintain immunological tolerance and can be harnessed to control autoimmunity and prevent transplant rejection. However, clinical trials w...

Background. In type 1 diabetes (T1D), insulin-producing pancreatic β cells are destroyed by CD4+ and CD8+ autoreactive T cells. Antigen-specific tolerance is desirable for T1D immunotherapy to avoid generalised immunosuppression. Our vaccine strategy uses liposome nanocarriers encapsulating disease...

Molecular mechanisms triggering the onset of islet autoimmunity and progression to clinically overt type 1 diabetes (T1D) remain poorly understood. microRNAs (miRNAs) critically regulate immune homeostasis. While profiles of total miRNA abundance in T-cells have been reported previously, none have ...

Background: FOXP3-positive regulatory T cells (Tregs) are important for maintaining peripheral immune tolerance. Multiple lines of evidence suggest that the dysfunction of Tregs plays a key role in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, previous studies a...

 Auto-reactive CD8 T-cells play an important role in the destruction of pancreatic β-cells resulting in type 1 diabetes (T1D). However, the phenotype of these auto-reactive cytolytic CD8 T-cells has not yet been extensively described. We used high-dimensional mass cytometry to phenotype auto- (pre...

Objective: T-cell-mediated destruction of pancreatic β cells leads to Type 1 diabetes Mellitus (TIDM). Tetraspanin-7(TSPAN7) has recently been identified as an autoantigen in T1DM patients. Autoreactive CD8+T cell recognize β-cell-derived epitopes in the context of major histocompatibility complex...