Fluvoxamine inhibits Th1 and Th17 polarization and function by repressing glycolysis to attenuate autoimmune progression in type 1 diabetes.

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULT: Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved ß cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. CONCLUSION: Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

ALDH2 deficiency exacerbates MCD-diet induced MASLD by modulating bile acid metabolism.

Aldehyde dehydrogenase 2 (ALDH2), an acetaldehyde dehydrogenase in mitochondria, is primarily responsible for metabolizing alcohol-derived acetaldehyde and other endogenous aldehydes. Inactivating ALDH2 rs671 polymorphism is found in up to 8 % of the global population and 40 % of the East Asian population. Recent studies have shown that rs671 SNP mutation in the human ALDH2 gene is associated with an increased risk of metabolic dysfunction-associated steatotic liver diseases (MASLD), but the mechanism remains unclear. Here, we identify the role of ALDH2 in MASLD. Firstly, ALDH2 activity was lower in MASLD patients and the methionine-choline deficiency (MCD) diet induced MASLD model. Secondly, activation of ALDH2 activity with Alda-1 (ALDH2 agonist) attenuated MCD-diet induced hepatic triglyceride (TG) accumulation and steatosis, whereas the opposite result was observed with cyanamide (CYA, ALDH2 inhibitor). Furthermore, ALDH2 deficiency exacerbated hepatic steatosis, inflammation, and fibrosis in the MCD-diet induced mice. RNA sequencing (RNA-seq) revealed that oxysterol 7-α hydroxylase (Cyp7b1) and the related metabolic pathway significantly changed in the MCD-diet challenged ALDH2-/- mice. In ALDH2-/- mice, the expression of Cyp7b1 was downregulated and FXR/SHP signaling was inhibited, reducing the alternative bile acid (BA) synthetic pathway. In our in vitro experiments, knockdown of ALDH2 exacerbated TG accumulation in hepatocytes, whereas the opposite result was observed with overexpression of ALDH2. Moreover, chenodeoxycholic acid (CDCA) rescued ALDH2 downregulation induced TG accumulation in hepatocytes. Our study reveals that ALDH2 attenuates hepatocyte steatosis by regulating the alternative BA synthesis pathway, and ALDH2 may serve as a potential target for the treatment of MASLD.

Ubc9 regulates the expression of MHC II in dendritic cells to enhance DSS-induced colitis by mediating RBPJ SUMOylation.

SUMOylation is an evolutionary conserved regulatory mechanism, in which Ubc9 is the only E2 conjugating enzyme. Previous studies demonstrated that SUMOylation is involved in multiple biological processes, but its role in dendritic cells (DCs) remains to be fully addressed. Herein in this report, we found that DCs deficient in Ubc9 protected mice from dextran sulfate sodium (DSS)-induced colitis, as evidenced by the ameliorated weight loss, colon length, and disrupted colon structure. Mechanistically, Ubc9 mediated SUMOylation of RBPJ, by which it stabilized RBPJ from ubiquitin-mediated degradation to enhance its transcriptional activity, while Ciita, a critical transcription factor, is a direct target downstream of RBPJ, which forms an enhanceosome complex to transcribe the expression of MHC II genes. Therefore, loss of Ubc9 abolished RBPJ SUMOylation, which was coupled with reduced Ciita transcription, thereby attenuating the expression of MHC class II genes. As a consequence of defective MHC II expression, Ubc9-/- DCs were featured by the impaired capability to process antigen and to prime effector CD4+ T cells, thereby protecting mice from DSS-induced colitis. Together, our results shed novel insight into the understanding of SUMOylation in the regulation of DC functions in pathological conditions.

Time to establish an international vaccine candidate pool for potential highly infectious respiratory disease: a community's view.

In counteracting highly infectious and disruptive respiratory diseases such as COVID-19, vaccination remains the primary and safest way to prevent disease, reduce the severity of illness, and save lives. Unfortunately, vaccination is often not the first intervention deployed for a new pandemic, as it takes time to develop and test vaccines, and confirmation of safety requires a period of observation after vaccination to detect potential late-onset vaccine-associated adverse events. In the meantime, nonpharmacologic public health interventions such as mask-wearing and social distancing can provide some degree of protection. As climate change, with its environmental impacts on pathogen evolution and international mobility continue to rise, highly infectious respiratory diseases will likely emerge more frequently and their impact is expected to be substantial. How quickly a safe and efficacious vaccine can be deployed against rising infectious respiratory diseases may be the most important challenge that humanity will face in the near future. While some organizations are engaged in addressing the World Health Organization's "blueprint for priority diseases", the lack of worldwide preparedness, and the uncertainty around universal vaccine availability, remain major concerns. We therefore propose the establishment of an international candidate vaccine pool repository for potential respiratory diseases, supported by multiple stakeholders and countries that contribute facilities, technologies, and other medical and financial resources. The types and categories of candidate vaccines can be determined based on information from previous pandemics and epidemics. Each participant country or region can focus on developing one or a few vaccine types or categories, together covering most if not all possible potential infectious diseases. The safety of these vaccines can be tested using animal models. Information for effective candidates that can be potentially applied to humans will then be shared across all participants. When a new pandemic arises, these pre-selected and tested vaccines can be quickly tested in RCTs for human populations.

Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset.

The regulation of autoimmunity against pancreatic islet ß cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.

CCR2 is a host entry receptor for severe fever with thrombocytopenia syndrome virus.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus causing a high fatality rate of up to 30%. To date, the receptor mediating SFTSV entry remained uncharacterized, hindering the understanding of disease pathogenesis. Here, C-C motif chemokine receptor 2 (CCR2) was identified as a host receptor for SFTSV based on a genome-wide CRISPR-Cas9 screen. Knockout of CCR2 substantially reduced viral binding and infection. CCR2 enhanced SFTSV binding through direct binding to SFTSV glycoprotein N (Gn), which is mediated by its N-terminal extracellular domain. Depletion of CCR2 in C57BL/6J mouse model attenuated SFTSV replication and pathogenesis. The peripheral blood primary monocytes from elderly individuals or subjects with underlying diabetes mellitus showed higher CCR2 surface expression and supported stronger binding and replication of SFTSV. Together, these data indicate that CCR2 is a host entry receptor for SFTSV infection and a novel target for developing anti-SFTSV therapeutics.

Pancreatic draining lymph nodes (PLNs) serve as a pathogenic hub contributing to the development of type 1 diabetes.

Type 1 diabetes (T1D) is a chronic, progressive autoinflammatory disorder resulting from the breakdown of self-tolerance and unrestrained ß cell-reactive immune response. Activation of immune cells is initiated in islet and amplified in lymphoid tissues, especially those pancreatic draining lymph nodes (PLNs). The knowledge of PLNs as the hub of aberrant immune response is continuously being replenished and renewed. Here we provide a PLN-centered view of T1D pathogenesis and emphasize that PLNs integrate signal inputs from the pancreas, gut, viral infection or peripheral circulation, undergo immune remodeling within the local microenvironment and export effector cell components into pancreas to affect T1D progression. In accordance, we suggest that T1D intervention can be implemented by three major ways: cutting off the signal inputs into PLNs (reduce inflammatory ß cell damage, enhance gut integrity and control pathogenic viral infections), modulating the immune activation status of PLNs and blocking the outputs of PLNs towards pancreatic islets. Given the dynamic and complex nature of T1D etiology, the corresponding intervention strategy is thus required to be comprehensive to ensure optimal therapeutic efficacy.

Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency Inhibits Pathological Cardiac Hypertrophy.

BACKGROUND: Aberrant amino acid metabolism is implicated in cardiac hypertrophy, while the involvement of tryptophan metabolism in pathological cardiac hypertrophy remains elusive. Herein, we aimed to investigate the effect and potential mechanism of IDO1 (indoleamine 2,3-dioxygenase) and its metabolite kynurenine (Kyn) on pathological cardiac hypertrophy. METHODS: Transverse aortic constriction was performed to induce cardiac hypertrophy in IDO1-knockout (KO) mice and AAV9-cTNT-shIDO1 mice. Liquid chromatography-mass spectrometry was used to detect the metabolites of tryptophan-Kyn pathway. Chromatin immunoprecipitation assay and dual luciferase assay were used to validate the binding of protein and DNA. RESULTS: IDO1 expression was upregulated in both human and murine hypertrophic myocardium, alongside with increased IDO1 activity and Kyn content in transverse aortic constriction-induced mice's hearts using liquid chromatography-mass spectrometry analysis. Myocardial remodeling and heart function were significantly improved in transverse aortic constriction-induced IDO1-KO mice, but were greatly exacerbated with subcutaneous Kyn administration. IDO1 inhibition or Kyn addition confirmed the alleviation or aggravation of hypertrophy in cardiomyocyte treated with isoprenaline, respectively. Mechanistically, IDO1 and metabolite Kyn contributed to pathological hypertrophy via the AhR (aryl hydrocarbon receptor)-GATA4 (GATA binding protein 4) axis. CONCLUSIONS: This study demonstrated that IDO1 deficiency and consequent Kyn insufficiency can protect against pathological cardiac hypertrophy by decreasing GATA4 expression in an AhR-dependent manner.

MBD2 facilitates tumor metastasis by mitigating DDB2 expression.

Despite past extensive studies, the pathoetiologies underlying tumor metastasis remain poorly understood, which renders its treatment largely unsuccessful. The methyl-CpG-binding domain 2 (MBD2), a "reader" to interpret DNA methylome-encoded information, has been noted to be involved in the development of certain types of tumors, while its exact impact on tumor metastasis remains elusive. Herein we demonstrated that patients with LUAD metastasis were highly correlated with enhanced MBD2 expression. Therefore, knockdown of MBD2 significantly attenuated the migration and invasion of LUAD cells (A549 and H1975 cell lines) coupled with attenuated epithelial-mesenchymal transition (EMT). Moreover, similar results were observed in other types of tumor cells (B16F10). Mechanistically, MBD2 selectively bound to the methylated CpG DNA within the DDB2 promoter, by which MBD2 repressed DDB2 expression to promote tumor metastasis. As a result, administration of MBD2 siRNA-loaded liposomes remarkably suppressed EMT along with attenuated tumor metastasis in the B16F10 tumor-bearing mice. Collectively, our study indicates that MBD2 could be a promising prognostic marker for tumor metastasis, while administration of MBD2 siRNA-loaded liposomes could be a viable therapeutic approach against tumor metastasis in clinical settings.

UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer.

The role of tumor-associated macrophages (TAMs), along with the regulatory mechanisms underlying distinct macrophage activation states, remains poorly understood in prostate cancer (PCa). Herein, we report that PCa growth in mice with macrophage-specific Ubc9 deficiency is substantially suppressed compared with that in wild-type littermates, an effect partially ascribed to the augmented CD8+ T cell response. Biochemical and molecular analyses revealed that signal transducer and activator of transcription 4 (STAT4) is a crucial UBC9-mediated SUMOylation target, with lysine residue 350 (K350) as the major modification site. Site-directed mutation of STAT4 (K350R) enhanced its nuclear translocation and stability, thereby facilitating the proinflammatory activation of macrophages. Importantly, administration of the UBC9 inhibitor 2-D08 promoted the antitumor effect of TAMs and increased the expression of PD-1 on CD8+ T cells, supporting a synergistic antitumor efficacy once it combined with the immune checkpoint blockade therapy. Together, our results demonstrate that ablation of UBC9 could reverse the immunosuppressive phenotype of TAMs by promoting STAT4-mediated macrophage activation and macrophage-CD8+ T cell crosstalk, which provides valuable insights to halt the pathogenic process of tumorigenesis.

SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance.

OBJECTIVE: As the only E2 conjugating enzyme for the SUMO system, Ubc9-mediated SUMOylation has been recognized to regulate diverse biological processes, but its impact on adipocytes relevant to obesity and insulin resistance is yet to be elucidated. METHODS: We established adipocyte-specific Ubc9 deficient mice to explore the effects of Ubc9 on obesity and metabolic disorders induced by high-fat diet (HFD) in adult mice. The molecular targets of SUMOylation were explored by liquid chromatography-mass spectrometry, and the regulatory mechanism of SUMOylation in T2D was analyzed. RESULTS: Adipocyte-specific depletion of Ubc9 (AdipoQ-Cre-Ubc9fl/fl, Ubc9AKO) protected mice from HFD-induced obesity, insulin resistance, and hepatosteatosis. The Ubc9AKO mice were featured by the reduced HFD-induced endoplasmic reticulum (ER) stress and inflammatory response. Mechanically, over nutrition rendered adipocytes to undergo a SUMOylation turnover characterized by the change of SUMOylation levels and substrates. ERp44 displayed the highest change in terms of SUMOylation levels of substrates involved in ER-related functions. The lack of ERp44 SUMOylation at lysine 76 (K76) located within the thioredoxin (TRX)-like domain by Ubc9 deficiency enhanced its degradation and suppressed its covalent binding to Ero1α, an oxidase that exists in the ER but lacks ER retention motif, thereby alleviating endoplasmic reticulum stress by promoting Ero1α secretion. CONCLUSIONS: Our data suggest that modulation of ERp44 SUMOylation in adipocytes could be a feasible strategy against obesity and insulin resistance in clinical settings.

Dietary selenomethionine attenuates obesity by enhancing beiging process in white adipose tissue.

Imbalanced nutrient intake causes abnormal energy metabolism, which results in obesity. There is feasible evidence that selenium-rich (Se-rich) foods may alleviate obesity and enhance general public health, but the underlying mechanisms remain elusive. Herein we examined the effect of Se supplementation on white adipose tissue beiging process. The mice were fed with a normal diet or a Se-deficient high-fat diet (DHFD) until significant differences in terms of body weight, glucose tolerance and insulin sensitivity. Next, mice in the DHFD group were changed to a high-fat diet (HFD) containing specified amounts of selenomethionine (SeMet) (0, 150, 300, and 600 µg/kg) and continued to feed for 14 weeks. Notably, 150 µg/kg SeMet supplement highly protected mice from DHFD-induced obesity, insulin resistance, and lipid deposits in the liver and kidney, and featured by the enhanced beiging process in white adipose tissue and increased energy expenditure. Moreover, upon cold challenge, 150 µg/kg SeMet supplement enhanced cold tolerance in mice by inducing adipose beiging to promote energy expenditure, as evidenced by the increased expression of uncoupling protein-1 (UCP1) in adipocytes. Similarly, SeMet (10 µM) promoted the differentiation of beige adipocytes from the stromal vascular fraction. Collectively, our data support that optimal supplementation of SeMet could enhance the beiging process to attenuate HFD-induced obesity, which provides new insights into the relationship between dietary SeMet and type 2 diabetes.

Comparative analysis of visual quality between unilateral implantation of a trifocal intraocular lens and a rotationally asymmetric refractive multifocal intraocular lens.

AIM: To compare visual quality after unilateral cataract surgery with implantation of trifocal intraocular lens (IOL) and asymmetric refractive multifocal IOL. METHODS: The prospective nonrandom, comparative study consisted of 60 eyes of 60 patients suffering unilateral cataract surgery with implantation of two different IOLs: AT LISA tri 839MP (30 eyes; Carl Zeiss Meditec, Germany) and LS-313 MF30 (30 eyes; Oculentis GmbH, Germany). Visual acuity, refractive outcome, contrast sensitivity, defocus curves, quality of vision, and optical phenomena were evaluated at 3mo postoperatively. RESULTS: There were no statistical differences between groups in uncorrected distance visual acuity (P=0.13) and uncorrected near visual acuity (P=0.54). In contrast, uncorrected intermediate visual acuity was better in trifocal group compared to the refractive multifocal group (P=0.02). No significant statistical between-group difference was detected in cylinder (P=0.43). Compared to trifocal group, spherical refraction and spherical equivalent in refractive multi focal group were more myopic (P<0.01). Under photopic conditions, no significant statistical differences were found between groups in contrast sensitivity at 3 and 6 cycles per degree (cpd). The refractive multifocal group performed better at 12 and 18 cpd than the trifocal group (P=0.01, P=0.034, respectively). The questionnaires of quality of vision and optical phenomena showed no differences between groups. CONCLUSION: Trifocal IOL is superior to refractive multifocal IOL in intermediate visual acuity. Rotationally asymmetric refractive multifocal IOL is more myopic in automated refraction and significantly better for the photopic contrast sensitivity at high frequency.

Blockade of Mbd2 by siRNA-loaded liposomes protects mice against OVA-induced allergic airway inflammation via repressing M2 macrophage production.

Objective: To address the role of methyl-CpG-binding domain 2 (MBD2) in the pathogenesis of asthma and its potential as a target for the asthmatic therapy. Methods: Studies were conducted in asthmatic patients and macrophage-specific Mbd2 knockout mice to dissect the role of MBD2 in asthma pathogenesis. Additionally, RNAi-based therapy with Mbd2 siRNA-loaded liposomes was conducted in an ovalbumin (OVA)-induced allergic airway inflammation mouse model. Results: Asthmatic patients and mice challenged with OVA exhibited upregulated MBD2 expression in macrophages, especially in alternatively activated (M2) macrophages. In particular, macrophage-specific knockout of Mbd2 protected mice from OVA-induced allergic airway inflammation and suppressed the M2 program. Notably, intratracheal administration of liposomes carrying Mbd2 siRNA decreased the expression of Mbd2 and prevented OVA-induced allergic airway inflammation in mice, as indicated by the attenuated airway inflammation and mucus production. Conclusions: The above data indicate that Mbd2 implicates in the pathogenesis of asthma predominantly by regulating the polarization of M2 macrophages, which supports that Mbd2 could be a viable target for treatment of asthma in clinical settings.

The interferon regulatory factors, a double-edged sword, in the pathogenesis of type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease resulted from the unrestrained inflammatory attack towards the insulin-producing islet ß cells. Although the exact etiology underlying T1D remains elusive, viral infections, especially those specific strains of enterovirus, are acknowledged as a critical environmental cue involved in the early phase of disease initiation. Viral infections could either directly impede ß cell function, or elicit pathological autoinflammatory reactions for ß cell killing. Autoimmune responses are bolstered by a massive body of virus-derived exogenous pathogen-associated molecular patterns (PAMPs) and the presence of ß cell-derived damage-associated molecular patterns (DAMPs). In particular, the nucleic acid components and the downstream nucleic acid sensing pathways serve as the major effector mechanism. The endogenous retroviral RNA, mitochondrial DNA (mtDNA) and genomic fragments generated by stressed or dying ß cells induce host responses reminiscent of viral infection, a phenomenon termed as viral mimicry during the early stage of T1D development. Given that the interferon regulatory factors (IRFs) are considered as hub transcription factors to modulate immune responses relevant to viral infection, we thus sought to summarize the critical role of IRFs in T1D pathogenesis. We discuss with focus for the impact of IRFs on the sensitivity of ß cells to cytokine stimulation, the vulnerability of ß cells to viral infection/mimicry, and the intensity of immune response. Together, targeting certain IRF members, alone or together with other therapeutics, could be a promising strategy against T1D.

The Essential Role of FoxO1 in the Regulation of Macrophage Function.

Macrophages are widely distributed in various tissues and organs. They not only participate in the regulation of innate and adaptive immune response, but also play an important role in tissue homeostasis. Dysregulation of macrophage function is closely related to the initiation, development and prognosis of multiple diseases, including infection and tumorigenesis. Forkhead box transcription factor O1 (FoxO1) is an important member among the forkhead box transcription factor family. Through directly binding to the promoter regions of downstream target genes, FoxO1 is implicated in cell proliferation, apoptosis, metabolic activities and other biological processes. In this review, we summarized the regulatory role of FoxO1 in macrophage phagocytosis, migration, differentiation and inflammatory activation. We also emphasized that macrophage reciprocally modulated FoxO1 activity via a post-translational modification (PTM) dominant manner.

Hydrophobic versus hydrophilic acrylic intraocular lens on posterior capsule opacification: a Meta-analysis.

AIM: To conduct a Meta-analysis pooling randomized controlled trials (RCTs) to compare hydrophobic with hydrophilic acrylic intraocular lenses in terms of posterior capsule opacification (PCO) development. METHODS: Electronic databases including PubMed, Embase, and the Cochrane Library were queried from their starting till January 2020. RCTs investigating the impact of hydrophobic versus hydrophilic acrylic intraocular lenses on PCO were considered eligible in this study. The pooled effect estimates were calculated using the random-effects model. RESULTS: Thirteen RCTs comprising of 939 patients (1263 eyes) were covered in this study. Patients with hydrophobic acrylic intraocular lenses had a lower PCO score than those with a hydrophilic acrylic intraocular lenses [standard mean difference: -1.80; 95% confidence interval (CI): -2.62 to -0.98; P<0.001]. Moreover, the frequency of neodymium-doped yttrium aluminum garnet (Nd:YAG) capsulotomy in patients with hydrophobic acrylic intraocular lenses was significantly lower than patients with hydrophilic acrylic intraocular lenses (relative risk: 0.38; 95%CI: 0.20-0.71; P=0.003). CONCLUSION: These findings suggest that hydrophobic acrylic intraocular lenses are superior to hydrophilic acrylic intraocular lenses in patients after cataract surgery due to lower PCO score and reduced Nd:YAG capsulotomy. While similar studies are conducted by other researchers, the present study conducted subgroup analyses that show superior results with hydrophobic lenses in trials conducted in western countries.

Lymphotoxins Serve as a Novel Orchestrator in T1D Pathogenesis.

Type 1 diabetes (T1D) stems from pancreatic ß cell destruction by islet reactive immune cells. Similar as other autoimmune disorders, there is no curative remedy for T1D thus far. Chronic insulitis is the hallmark of T1D, which creates a local inflammatory microenvironment that impairs ß cell function and ultimately leads to ß cell death. Immune regulation shows promise in T1D treatment by providing a time window for ß cell recovery. However, due to the complex nature of T1D pathogenesis, the therapeutic effect of immune regulation is often short-lasting and unsatisfying in monotherapies. Lymphotoxins (LTs) were first identified in 1960s as the lymphocyte-producing cytokine that can kill other cell types. As a biological cousin of tumor necrosis factor alpha (TNFα), LTs play unique roles in T1D development. Herein in this review, we summarized the advancements of LTs in T1D pathogenesis. We particularly highlighted their effect on the formation of peri-islet tertiary lymphoid organs (TLOs), and discussed their synergistic effect with other cytokines on ß cell toxicity and autoimmune progression. Given the complex and dynamic crosstalk between immune cells and ß cells in T1D setting, blockade of lymphotoxin signaling applied to the existing therapies could be an efficient approach to delay or even reverse the established T1D.