Beta cells deficient for counteract autoimmunity by shaping natural killer cell activity.

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells.

Renalase inhibition regulates β cell metabolism to defend against acute and chronic stress.

Renalase (Rnls), annotated as an oxidase enzyme, is a GWAS gene associated with Type 1 Diabetes (T1D) risk. We previously discovered that Rnls inhibition delays diabetes onset in mouse models of T1D , and protects pancreatic β cells against autoimmune killing, ER and oxidative stress . The molecular biochemistry and functions of Rnls are entirely uncharted.

Beta Cells Deficient for Counteract Autoimmunity by Shaping Natural Killer Cell Activity.

Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Recent advancements in the technology of generating pancreatic beta cells from human pluripotent stem cells (SC-beta cells) have facilitated the exploration of cell replacement therapies for treating T1D. However, the persistent threat of autoimmunity poses a significant challenge to the survival of transplanted SC-beta cells.

Protective Renalase Deficiency in β-Cells Shapes Immune Metabolism and Function in Autoimmune Diabetes.

Unlabelled: Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic β-cells that produce insulin. The latest advances in stem cell (SC) β-cell differentiation methods have made a cell replacement therapy for T1D feasible. However, recurring autoimmunity would rapidly destroy transplanted SC β-cells.

Gata3 is detrimental to regulatory T cell function in autoimmune diabetes.

Regulatory T cells (Tregs) protect against autoimmunity. In type 1 diabetes (T1D), Tregs slow the progression of beta cell autoimmunity within pancreatic islets. Increasing the potency or frequency of Tregs can prevent diabetes, as evidenced by studies in the nonobese diabetic (NOD) mouse model for T1D.

Bioluminescent Monitoring of Graft Survival in an Adoptive Transfer Model of Autoimmune Diabetes in Mice.

Type 1 diabetes is characterized by the autoimmune destruction of the insulin-producing beta cells of the pancreas. A promising treatment for this disease is the transplantation of stem cell-derived beta cells. Genetic modifications, however, may be necessary to protect the transplanted cells from persistent autoimmunity.

CD5 Controls Gut Immunity by Shaping the Cytokine Profile of Intestinal T Cells.

CD5 is constitutively expressed on all T cells and is a negative regulator of lymphocyte function. However, the full extent of CD5 function in immunity remains unclear. CD5 deficiency impacts thymic selection and extra-thymic regulatory T cell generation, yet CD5 knockout was reported to cause no immune pathology.

Genetic Modifiers of Thymic Selection and Central Tolerance in Type 1 Diabetes.

Type 1 diabetes (T1D) is caused by the T cell-driven autoimmune destruction of insulin-producing cells in the pancreas. T1D served as the prototypical autoimmune disease for genome wide association studies (GWAS) after having already been the subject of many linkage and association studies prior to the development of GWAS technology. Of the many T1D-associated gene variants, a minority appear disease-specific, while most are shared with one or more other autoimmune condition.

Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes.

Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic beta cells. Pluripotent stem cells can now be differentiated into beta cells, thus raising the prospect of a cell replacement therapy for T1D. However, autoimmunity would rapidly destroy newly transplanted beta cells.

Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice.

Purpose: A coding variant in PTPN22 (C1858T) is one of the most important genetic risk factors in type 1 diabetes (T1D). The role of the PTPN22 risk allele in B cells is still incompletely understood and has not been investigated directly in T1D. This study aimed to explore the role of PTPN22 in the homeostasis of B cells and its influence in T1D.

Collective cancer invasion forms an integrin-dependent radioresistant niche.

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive.

Anti-CD3 Antibody for the Prevention of Type 1 Diabetes: A Story of Perseverance.

Type 1 diabetes (T1D) is an autoimmune disease characterized by an insulin deficiency. Ever since the discovery of insulin almost 100 years ago, patients with T1D have relied on multiple daily insulin injections to survive an otherwise deadly disease. Despite decades of research and clinical trials, no treatment exists yet to prevent or cure T1D.

The type 1 diabetes candidate gene Dexi does not affect disease risk in the nonobese diabetic mouse model.

Genome-wide association studies have implicated more than 50 genomic regions in type 1 diabetes (T1D). A T1D region at chromosome 16p13.13 includes the candidate genes CLEC16A and DEXI.

Increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes.

Type 1 diabetes (T1D) is characterized by pancreatic islet infiltration by autoreactive immune cells and a near-total loss of β-cells. Restoration of insulin-producing β-cells coupled with immunomodulation to suppress the autoimmune attack has emerged as a potential approach to counter T1D. Here we report that enhancing β-cell mass early in life, in two models of female NOD mice, results in immunomodulation of T-cells, reduced islet infiltration and lower β-cell apoptosis, that together protect them from developing T1D.

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity.

Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene , which encodes TAGAP, a guanosine triphosphatase (GTPase)-activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes' adhesion to the cortex through their β-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection.

Peripherally induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model.

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3 regulatory T-cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3 Tregs is generated in the periphery (pTregs) from Foxp3 CD4 T-cell precursors.

In Vivo Enrichment of Diabetogenic T Cells.

Dysfunctional T cells can mediate autoimmunity, but the inaccessibility of autoimmune tissues and the rarity of autoimmune T cells in the blood hinder their study. We describe a method to enrich and harvest autoimmune T cells in vivo by using a biomaterial scaffold loaded with protein antigens. In model antigen systems, we found that antigen-specific T cells become enriched within scaffolds containing their cognate antigens.

Ptpn22 Modifies Regulatory T Cell Homeostasis via GITR Upregulation.

PTPN22 gene variation associates with multiple autoimmune diseases, including type 1 diabetes and rheumatoid arthritis. Loss of function studies have demonstrated that PTPN22 impinges on the homeostatic behavior of regulatory T (Treg) cells, a lineage critical for immune tolerance. The frequency and absolute number of Treg cells is increased in Ptpn22-deficient mice, but the mechanism driving this increase is unknown.

Deficiency of HIF1α in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice.

Objective: Although immune responses drive the pathogenesis of atherosclerosis, mechanisms that control antigen-presenting cell (APC)-mediated immune activation in atherosclerosis remain elusive. We here investigated the function of hypoxia-inducible factor (HIF)-1α in APCs in atherosclerosis.

Approach And Results: We found upregulated HIF1α expression in CD11c(+) APCs within atherosclerotic plaques of low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice.

The Autoimmunity-Associated Gene CLEC16A Modulates Thymic Epithelial Cell Autophagy and Alters T Cell Selection.

CLEC16A variation has been associated with multiple immune-mediated diseases, including type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, celiac disease, Crohn's disease, Addison's disease, primary biliary cirrhosis, rheumatoid arthritis, juvenile idiopathic arthritis, and alopecia areata. Despite strong genetic evidence implicating CLEC16A in autoimmunity, this gene's broad association with disease remains unexplained. We generated Clec16a knock-down (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes and found that Clec16a silencing protected against autoimmunity.

PTPN22 silencing in the NOD model indicates the type 1 diabetes-associated allele is not a loss-of-function variant.

PTPN22 encodes the lymphoid tyrosine phosphatase (LYP) and is the second strongest non-HLA genetic risk factor for type 1 diabetes. The PTPN22 susceptibility allele generates an LYP variant with an arginine-to-tryptophan substitution at position 620 (R620W) that has been reported by several studies to impart a gain of function. However, a recent report investigating both human cells and a knockin mouse model containing the R620W homolog suggested that this variation causes faster protein degradation.

IL-17 silencing does not protect nonobese diabetic mice from autoimmune diabetes.

The long-held view that many autoimmune disorders are primarily driven by a Th1 response has been challenged by the discovery of Th17 cells. Since the identification of this distinct T cell subset, Th17 cells have been implicated in the pathogenesis of several autoimmune diseases, including multiple sclerosis and rheumatoid arthritis. Type 1 diabetes has also long been considered a Th1-dependent disease.

From genome-wide association studies to etiology: probing autoimmunity genes by RNAi.

Autoimmunity cannot yet be prevented or cured, in large part due to our poor understanding of disease etiology. Remarkable advances in genomic technology have recently enabled the discovery of a large number of disease-associated gene variations by genome-wide association studies. The next step towards understanding autoimmune disorders entails the functional study of susceptibility genes within experimental disease models.

The soluble CTLA-4 splice variant protects from type 1 diabetes and potentiates regulatory T-cell function.

Objective: CTLA4 gene variation associates with multiple autoimmune disorders, including type 1 diabetes. The CTLA4 susceptibility allele was found to generate decreased levels of mRNA encoding soluble CTLA-4 (sCTLA-4) relative to the full-length isoform, the functional consequence of which is as yet unknown. In this study, we investigated the contribution of sCTLA-4 to immune regulation with the aim to elucidate the functional basis of the disease association of CTLA4.