Cells In Autoimmune Diabetes Research Articles

Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice.

Haploinsufficiency of the transcription factor interferon-regulatory factor 4 (IRF4) prevents the onset of spontaneous diabetes in NOD mice. However, the immunological mechanisms of the IRF4-mediated disease regulation remain unclear. This study aims to investigate the role of IRF4 in the pathogenesis of autoimmune diabetes by conducting adoptive transfer experiments using donor IRF4 gene-deficient CD4+ T cells from BDC2.5-transgenic (Tg) NOD mice and recipient Rag1-knockout NOD mice, respectively. Through this approach, we analyzed both clinical and immunological phenotypes of the recipient mice. Additionally, IRF4-deficient BDC2.5 CD4+ T cells were stimulated to assess their immunological and metabolic phenotypes in vitro. The findings revealed that diabetes was completely prevented in the recipients with Irf4-/- T cells and was approximately 50% lower in those with Irf4+/- T cells than in wild type (WT) controls, whereas Irf4-/- recipients with WT T cells only showed a delayed onset of diabetes. Islet-infiltrating T cells isolated from recipients with Irf4+/- T cells exhibited significantly lower proliferation and IFN-γ/IL-17 double-positive cell fraction rates compared with those in WT controls. Irf4-/- BDC2.5 CD4+ T cells stimulated in vitro showed a reduced number of cell divisions, decreased antigen-specific T-cell markers, and impairment of glycolytic capacity compared with those observed in WT controls. We concluded that IRF4 predominantly regulates the diabetogenic potential in a dose-dependent manner by mediating the proliferation and differentiation of islet-infiltrating T cells while playing an adjunctive role in the innate immune responses toward diabetes progression in NOD mice.

TIGIT acts as an immune checkpoint upon inhibition of PD1 signaling in autoimmune diabetes.

Chronic activation of self-reactive T cells with beta cell antigens results in the upregulation of immune checkpoint molecules that keep self-reactive T cells under control and delay beta cell destruction in autoimmune diabetes. Inhibiting PD1/PD-L1 signaling results in autoimmune diabetes in mice and humans with pre-existing autoimmunity against beta cells. However, it is not known if other immune checkpoint molecules, such as TIGIT, can also negatively regulate self-reactive T cells. TIGIT negatively regulates the CD226 costimulatory pathway, T-cell receptor (TCR) signaling, and hence T-cell function. The phenotype and function of TIGIT expressing islet infiltrating T cells was studied in non-obese diabetic (NOD) mice using flow cytometry and single cell RNA sequencing. To determine if TIGIT restrains self-reactive T cells, we used a TIGIT blocking antibody alone or in combination with anti-PDL1 antibody. We show that TIGIT is highly expressed on activated islet infiltrating T cells in NOD mice. We identified a subset of stem-like memory CD8+ T cells expressing multiple immune checkpoints including TIGIT, PD1 and the transcription factor EOMES, which is linked to dysfunctional CD8+ T cells. A known ligand for TIGIT, CD155 was expressed on beta cells and islet infiltrating dendritic cells. However, despite TIGIT and its ligand being expressed, islet infiltrating PD1+TIGIT+CD8+ T cells were functional. Inhibiting TIGIT in NOD mice did not result in exacerbated autoimmune diabetes while inhibiting PD1-PDL1 resulted in rapid autoimmune diabetes, indicating that TIGIT does not restrain islet infiltrating T cells in autoimmune diabetes to the same degree as PD1. Partial inhibition of PD1-PDL1 in combination with TIGIT inhibition resulted in rapid diabetes in NOD mice. These results suggest that TIGIT and PD1 act in synergy as immune checkpoints when PD1 signaling is partially impaired. Beta cell specific stem-like memory T cells retain their functionality despite expressing multiple immune checkpoints and TIGIT is below PD1 in the hierarchy of immune checkpoints in autoimmune diabetes.

Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes.

SUMMARYType 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.

Mast Cells and the Pancreas in Human Type 1 and Type 2 Diabetes

Mast cells are highly differentiated, widely distributed cells of the innate immune system, that are currently considered as key regulators of both innate and adaptive immunity. Mast cells play a key role in health and survival mechanisms, especially as sentinel cells that can stimulate protective immune responses. On the other hand, it has been shown that mast cells are involved in the pathogenesis of several diseases, and recently a possible pathogenetic role of mast cells in diabetes has been proposed. In this review we summarize the evidence on the increased presence of mast cells in the pancreas of subjects with type 1 diabetes, which is due to the autoimmune destruction of insulin secreting beta cells, and discuss the differences with type 2 diabetes, the other major form of diabetes. In addition, we describe some of the pathophysiological mechanisms through which mast cells might exert their actions, which could be targeted to potentially protect the beta cells in autoimmune diabetes.

Tolerance to Proinsulin-1 Reduces Autoimmune Diabetes in NOD Mice.

T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice.

Proinflammatory Signaling in Islet β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes

Proinflammatory Signaling in Islet β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes

NKG2D Signaling Within the Pancreatic Islets Reduces NOD Diabetes and Increases Protective Central Memory CD8+ T-Cell Numbers.

NKG2D is implicated in autoimmune diabetes. However, the role of this receptor in diabetes pathogenesis is unclear owing to conflicting results with studies involving global inhibition of NKG2D signaling. We found that NKG2D and its ligands are present in human pancreata, with expression of NKG2D and its ligands increased in the islets of patients with type 1 diabetes. To directly assess the role of NKG2D in the pancreas, we generated NOD mice that express an NKG2D ligand in β-islet cells. Diabetes was reduced in these mice. The reduction corresponded with a decrease in the effector to central memory CD8+ T-cell ratio. Further, NKG2D signaling during in vitro activation of both mouse and human CD8+ T cells resulted in an increased number of central memory CD8+ T cells and diabetes protection by central memory CD8+ T cells in vivo. Taken together, these studies demonstrate that there is a protective role for central memory CD8+ T cells in autoimmune diabetes and that this protection is enhanced with NKG2D signaling. These findings stress the importance of anatomical location when determining the role NKG2D signaling plays, as well as when developing therapeutic strategies targeting this pathway, in type 1 diabetes development.

Mechanosensing through YAP controls T cell activation and metabolism.

Upon immunogenic challenge, lymph nodes become mechanically stiff as immune cells activate and proliferate within their encapsulated environments, and with resolution, they reestablish a soft baseline state. Here we show that sensing these mechanical changes in the microenvironment requires the mechanosensor YAP. YAP is induced upon activation and suppresses metabolic reprogramming of effector T cells. Unlike in other cell types in which YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT1 into the nucleus. YAP slows T cell responses in systemic viral infections and retards effector T cells in autoimmune diabetes. Our work reveals a paradigm whereby tissue mechanics fine-tune adaptive immune responses in health and disease.

Enhanced N-glycan branching on CD8 T cells exacerbates autoimmune diabetes in non-obese diabetic mice

Abstract β1,6N-acetylglucosaminyltransferase V (Mgat5), is responsible for tetra-antennary N-glycans in the biosynthesis of glycoprotein and the resultant N-glycan branching serves as a backbone for additional glycosylation such as poly-N-aceyllactosamine (poly-LacNAc) structure. The N-glycan branching is involved in the pathological conditions such as malignancies, but the modulatory roles of N-glycan branching on T cells in autoimmune diabetes is not completely understood. Here, we report that the levels of N-glycan branching on T cells is positively correlated with the diabetogenesis in NOD mice. Since the levels of N-glycan branching is regulated during T-cell development and highly increases in pathogenic lymphocytes in pancreas, we generated established T cell-specific Mgat5 transgenic and mutant NOD mice. Interestingly, our results demonstrated that the diabetic incidence in Mgat5 transgenic mice was significantly higher and that of Mgat5 mutant mice markedly attenuated compared to control NOD mice. In adoptive transfer experiments, NOD/SCID mice that received control CD4 T cells plus transgenic CD8 T cells developed diabetes more rapidly than the mice received control or transgenic CD4 T cells plus control CD8 T cells, suggesting that the diabetogenicity in Mgat5 transgenic mice is a CD8 T cell–autonomous manner. Moreover, we generated Mgat5/NY8.3 doubly transgenic NOD mice expressing highly pathogenic MHC class-I-restricted 8.3 T cell receptor, and observed that these mice have higher diabetic incidence than wild-type NY8.3 transgenic NOD mice. Taken together, enhanced N-glycan branching on CD8 T cells exacerbates the development of diabetes in NOD mice.

Cluster of Differentiation 4 T Cells and Neoantigens in Autoimmune Diabetes

Our investigations of antigens for pathogenic T cells in autoimmune diabetes led to the discovery of hybrid insulin peptides as T cell epitopes. T cells reactive to hybrid insulin peptides can be found at high frequency in the nonobese diabetic mouse model of type 1 diabetes and are also present in human patients. Hybrid insulin peptides can also be administered to mice in a tolerogenic form, thereby suppressing the autoimmune response.

Hybrid insulin peptides are neo-epitopes for CD4 T cells in autoimmune diabetes.

The current review covers recent advances in our knowledge of the newest autoantigen neo-epitopes in type 1 diabetes (T1D): hybrid insulin peptides or HIPs. These ligands for autoreactive T cells are formed by peptide fusion, a novel posttranslational modification process that we first reported in 2016. Two major HIPs in the nonobese diabetic mouse model, ligands for diabetogenic CD4 T-cell clones, have been incorporated into tetramers and used to track HIP-reactive T cells during progression of disease. HIPs have also been used in strategies for induction of antigen-specific tolerance and show promise for delaying or reversing disease in the nonobese diabetic mouse. Importantly, CD4 T cells reactive to various HIPs have been detected in the islets and peripheral blood mononuclear cell of T1D patients and newly developed human T-cell clones are being employed to gather more data on the phenotype and function of HIP-reactive T cells in patients. These new hybrid insulin peptide epitopes may provide the basis for establishing autoreactive T cells as biomarkers of disease and as potential tolerogens for treatment of T1D.

91-OR: Stem Cell-Derived Tissue-Associated Regulatory T Cells Suppress the Activity of Pathogenic Immune Cells in Autoimmune Diabetes

The auto antigen (Ag)-specific regulatory T cells (Tregs) from pluripotent stem cells (PSCs), i.e., PSC-Tregs, have the ability to suppress autoimmunity. PSC-Tregs can be programmed to be tissue-associated and to infiltrate into local inflamed tissues to suppress autoimmune responses after adoptive transfer. Nevertheless, the mechanisms by which the auto Ag-specific PSC-Tregs suppress the autoimmune response remain to be fully elucidated. In this study, we generated the functional auto Ag-specific Tregs from the induced PSC (iPSCs), i.e., iPSC-Tregs, and investigated the underlying mechanisms of autoimmunity suppression by these Tregs in a type 1 diabetes (T1D) murine model. A double transgenic (Tg) mouse model of T1D was established in F1 mice in which the first generation of RIP-mOVA Tg mice that were crossed with OT-I T cell receptor (TCR) Tg mice was challenged with vaccinia viruses expressing OVA (VACV-OVA). We show that adoptive transfer of OVA-specific iPSC-Tregs greatly suppressed autoimmunity in the animal model and prevented the insulin-secreting pancreatic β cells from destruction. Further, we demonstrate that the adoptive transfer significantly reduced the expression of ICAM-1 in the diabetic pancreas and inhibited the migration of pathogenic CD8+ T cells and the production of the pro-inflammatory IFN-γ in the pancreas. These results indicate that the stem cell-derived tissue-associated Tregs can robustly accumulate in the diabetic pancreas, and through down-regulating the expression of ICAM-1 in the local inflamed tissues and inhibiting the production of pro-inflammatory cytokine IFN-γ, suppress the migration and activity of the pathogenic immune cells that cause T1D. Disclosure J.J. Song: None. Funding American Diabetes Association (1-16-IBS-281); National Institutes of Health (R01AI121180, R21AI109239)

Stem cell-derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes.

The autoantigen-specific Tregs from pluripotent stem cells (PSCs), i.e., PSC-Tregs, have the ability to suppress autoimmunity. PSC-Tregs can be programmed to be tissue associated and to infiltrate into local inflamed tissues to suppress autoimmune responses after adoptive transfer. Nevertheless, the mechanisms by which the autoantigen-specific PSC-Tregs suppress the autoimmune response remain to be fully elucidated. In this study, we generated functional autoantigen-specific Tregs from the induced PSC (iPSCs), i.e., iPSC-Tregs, and investigated the underlying mechanisms of autoimmunity suppression by these Tregs in a type 1 diabetes (T1D) murine model. A double-Tg mouse model of T1D was established in F1 mice, in which the first generation of RIP-mOVA Tg mice that were crossed with OT-I T cell receptor (TCR) Tg mice was challenged with vaccinia viruses expressing OVA (VACV-OVA). We show that adoptive transfer of OVA-specific iPSC-Tregs greatly suppressed autoimmunity in the animal model and prevented the insulin-secreting pancreatic β cells from destruction. Further, we demonstrate that the adoptive transfer significantly reduced the expression of ICAM-1 in the diabetic pancreas and inhibited the migration of pathogenic CD8+ T cells and the production of the proinflammatory IFN-γ in the pancreas. These results indicate that the stem cell-derived tissue-associated Tregs can robustly accumulate in the diabetic pancreas, and, through downregulating the expression of ICAM-1 in the local inflamed tissues and inhibiting the production of proinflammatory cytokine IFN-γ, suppress the migration and activity of the pathogenic immune cells that cause T1D.

Prenatal Betamethasone interferes with immune system development and alters target cells in autoimmune diabetes

Non-genetic factors are crucial in the pathogenesis of type 1 diabetes (T1D), a disease caused by autoimmunity against insulin-producing β-cells. Exposure to medications in the prenatal period may influence the immune system maturation, thus altering self-tolerance. Prenatal administration of betamethasone –a synthetic glucocorticoid given to women at risk of preterm delivery– may affect the development of T1D. It has been previously demonstrated that prenatal betamethasone administration protects offspring from T1D development in nonobese diabetic (NOD) mice. The direct effect of betamethasone on the immature and mature immune system of NOD mice and on target β-cells is analysed in this paper. In vitro, betamethasone decreased lymphocyte viability and induced maturation-resistant dendritic cells, which in turn impaired γδ T cell proliferation and decreased IL-17 production. Prenatal betamethasone exposure caused thymus hypotrophy in newborn mice as well as alterations in immune cells subsets. Furthermore, betamethasone decreased β-cell growth, reduced C-peptide secretion and altered the expression of genes related to autoimmunity, metabolism and islet mass in T1D target tissue. These results support the protection against T1D in the betamethasone-treated offspring and demonstrate that this drug alters the developing immune system and β-cells. Understanding how betamethasone generates self-tolerance could have potential clinical relevance in T1D.

PEP-1-paraoxonase 1 fusion protein prevents cytokine-induced cell destruction and impaired insulin secretion in rat insulinoma cells

Pancreatic beta cell destruction and dysfunction induced by cytokines is a major cause of type 1 diabetes. Paraoxonase 1 (PON1), an arylesterase with antioxidant activity, has been shown to play an important role in preventing the development of diabetes in transgenic mice. However, no studies have examined the anti-diabetic effect of PON1 delivered to beta cells using protein transduction. In this study, we expressed the cell-permeable PON1 fused with PEP-1 protein transduction domain (PEP-1-PON1) to investigate whether transduced PEP-1-PON1 protects beta cells against cytokine-induced cytotoxicity. PEP-1-PON1 was effectively delivered to INS-1 cells and prevented cytokine-induced cell destruction in a dose-dependent manner. Transduced PEP-1-PON1 significantly reduced the levels of reactive oxygen species (ROS) and nitric oxide (NO), DNA fragmentation, and expression of inflammatory mediators, endoplasmic reticulum (ER) stress proteins, and apoptosis-related proteins in cytokine-treated cells. Moreover, transduced PEP-1-PON1 restored the decrease in basal and glucose-stimulated insulin secretion induced by cytokines. These data indicate that PEP-1-PON1 protects beta cells from cytokine-induced cytotoxicity by alleviating oxidative/nitrosative stress, ER stress, and inflammation. Thus, PEP-1-mediated PON1 transduction might be an effective method to reduce the extent of destruction and dysfunction of pancreatic beta cells in autoimmune diabetes.

Self-Reactivity and T-Cell Receptor Repertoire of Effector and Regulatory T Cells in Autoimmune Diabetes

T cell infiltration and accumulation in pancreatic islets during autoimmune diabetes is to a large degree driven by TCR reactivity to beta cell antigens. However, it is not fully clear whether the strength of TCR reactivity to beta cell antigens is an important determinant of effector or regulatory T cell function. We observed that CD5 expression is proportional to the level of self-reactivity based on Nur77-GFP reporter of TCR signaling and insulin tetramer staining of islet infiltrating T cells. Using RNAseq profiling, TCR sequencing, and cell transfer we show that CD5 segregates functionally and transcriptionally distinct effector and regulatory T cells, demonstrating that reactivity to beta cell antigens is an important determinant of effector and regulatory T cell function in autoimmune diabetes. Disclosure Y. Kong: None. M.L. Sprouse: None. Y. Jing: None. M. Bettini: None. M. Bettini: None.

MDA5, a Janus-faced dsRNA sensor in Coxsackievirus-accelerated autoimmune diabetes

Abstract While microbial infections can trigger autoimmune diabetes, ultimately, innate immune activation and the synthesis of free radicals, proinflammatory cytokines, and Type I interferons contribute to pancreatic β-cell destruction in Type 1 diabetes (T1D). We previously demonstrated that Coxsackievirus B3 (CB3) infection of Non-Obese Diabetic (NOD) mice can accelerate T1D, partly due to the induction of oxidative stress and antiviral signaling pathways including melanoma differentiation-associated protein 5 (MDA5). Single-nucleotide polymorphisms within Ifih1, the gene encoding for MDA5, is associated with multiple autoimmune diseases including T1D, but the molecular mechanism contributing to innate immune dysregulation is not known. Since T1D is a chronic proinflammatory autoimmune disease involving MDA5, we hypothesized that aberrant MDA5 expression and signaling can contribute to diabetogenic viral-accelerated T1D. NOD mice mutated in Ifih1 that resulted in loss of MDA5 expression (NOD.Ifih1_m1) or an in-frame truncation in the helicase domain of MDA5 (NOD.Ifih1_m4) exhibited a delay in spontaneous T1D. Interestingly, CB3-infected NOD and NOD.Ifih1_m1 mice displayed accelerated virus-induced T1D, but NOD.Ifih1_m4 mice were significantly (p < 0.001) delayed. CB3-infected NOD.Ifih1_m4 mice were efficient in pancreatic viral clearance and exhibited decreases in circulating Type I interferons in contrast to NOD and NOD.Ifih1_m1 mice. The protective Ifih1_m4 mutation may establish an acute level of Type I interferons sufficient to inhibit CB3 replication without mediating bystander activation of autoreactive T cells in autoimmune diabetes.

Level of self-reactivity modulates functional potential of effector T cells in autoimmune diabetes.

Abstract T cell infiltration and accumulation in pancreatic islets during autoimmune diabetes is largely dependent on TCR specificity for beta cell antigens. However, it is not fully clear whether the level of self-reactivity is an important determinant of T cell function in autoimmunity. We observed that CD5 expression is proportional to the level of self-reactivity based on Nur77-GFP reporter of TCR signaling and insulin tetramer staining of islet infiltrating T cells. Using RNAseq profiling, TCR sequencing, and cell transfer diabetes model we show that CD5 segregates functionally and transcriptionally distinct effector T cells. Transfer of CD5hi islet infiltrating T cells resulted in accelerated diabetes development compared to CD5lo cells (8 weeks vs. 11 weeks post transfer), suggesting that both T cell populations are able to re-infiltrate the pancreas and cause beta cell destruction, but CD5hi T cells exhibit increased pathogenicity. RNAseq analysis showed an increase in expression of Lag3 and FR4 in CD5hi cells, consistent with their increased activation and subsequent induction of regulatory and tolerogenic pathways. However, cell intrinsic negative regulators did not suppress IFNg production in CD5hi T cells, which was significantly higher compared to CD5lo cells. Our findings show that the strength of TCR reactivity to beta cell antigens is an important determinant of T cell pathogenicity in autoimmune diabetes.

Papers of note in Science Immunology 2 (9)

This month’s articles show how an anti-inflammatory mediator is required for allergic responses, how targeting of the deacetylase Sirtuin 1 may provide a therapy against Mycobacterium tuberculosis infection, and how an inhibitory receptor limits the proliferation of regulatory T cells in autoimmune diabetes.

Deoxyhypusine Synthase Promotes Differentiation and Proliferation of T Helper Type 1 (Th1) Cells in Autoimmune Diabetes

In type 1 diabetes, cytokines arising from immune cells cause islet β cell dysfunction even before overt hyperglycemia. Deoxyhypusine synthase catalyzes the crucial hypusine modification of the factor eIF5A, which promotes the translation of a subset of mRNAs involved in cytokine responses. Here, we tested the hypothesis that deoxyhypusine synthase and, secondarily, hypusinated eIF5A contribute to the pathogenesis of type 1 diabetes using the non-obese diabetic (NOD) mouse model. Pre-diabetic NOD mice that received injections of the deoxyhypusine inhibitor N1-guanyl-1,7-diaminoheptane (GC7) demonstrated significantly improved glucose tolerance, more robust insulin secretion, and reduced insulitis compared with control animals. Analysis of tissues from treated mice revealed selective reductions in diabetogenic T helper type 1 (Th1) cells in the pancreatic lymph nodes, a primary site of antigen presentation. Isolated mouse CD90.2(+) splenocytes stimulated in vitro with anti-CD3/anti-CD28 and IL-2 to mimic autoimmune T cell activation exhibited proliferation and differentiation of CD4(+) T cell subsets (Th1, Th17, and Treg), but those treated with the deoxyhypusine synthase inhibitor GC7 showed a dose-dependent block in T cell proliferation with selective reduction in Th1 cells, similar to that observed in NOD mice. Inhibition of deoxyhypusine synthase blocked post-transcriptional expression of CD25, the high affinity IL-2 receptor α chain. Our results suggest a previously unrecognized role for deoxyhypusine synthase in promoting T cell proliferation and differentiation via regulation of CD25. Inhibition of deoxyhypusine synthase may provide a strategy for reducing diabetogenic Th1 cells and preserving β cell function in type 1 diabetes.