Splenocytes and thymocytes migration patterns between lymphoid organs in pregnancy.

Background: Cell migration is essential for the immune system and is frequently analyzed in adult non-pregnant animals but poorly explored in pregnant animals. However, a physiologic increased size in the spleen and periaortic lymph nodes had been reported in pregnant mice. Methods: Using a mouse model, we transferred PKH26-stained thymocytes and splenocytes from pregnant or non-pregnant animals to receptor mice in the presence or absence of pregnancy. Percentage of PKH-26 cells and Mean Fluorescence Intensity were calculated. Non-parametric ANOVA analysis was performed. Results: We detected that the percentage of PKH26+ thymocytes in the spleen, lymph nodes, and peripheral blood is higher in females than in males (p = 0.039). Our results showed a similar frequency of thymocytes and splenocytes from pregnant and non-pregnant mice located in receptor lymphoid organs (p > 0.05). Also, the location of marked cells was similar during the perinatal period (p > 0.05). Conclusions: The mobility of thymocytes and splenocytes in pregnant and non-pregnant mice is similar. Therefore, we suggest that the larger size of the spleen and periaortic lymph nodes noted previously in pregnant mice could result from the retention of leukocytes in the secondary lymphoid organs.

Adverse effects of cadmium on lymphoid organs, immune cells, and immunological responses.

Humans and animals possess robust immune systems to safeguard against foreign pathogens. However, recent reports suggest a greater incidence of immunity breakdown due to exposure to environmental pollutants, with heavy metals emerging as potential candidates in such immuno-toxicological studies. While we have extensive data on the general toxicity resulting from exposure to heavy metals, comprehensive documentation of their role as immune disruptors remains scarce. Cd (Cadmium) exerts immunomodulation by interfering with immune organs and cells, leading to altered structure, physiology, and function, thereby inducing symptoms of immune deregulation, inflammation and/or autoimmunity. This review aims to summarize the link between Cd exposure and immune dysfunction, drawing from case studies on exposed human subjects, as well as research conducted on various model organisms and in-vitro culture systems.

Wandering Spleen in a 47-year-old female treated by non-operative conservative management. Case report and literature review.

INTRODUCTION: Wandering spleen (WS) is a rare clinical condition found in less than 0.5 % of splenectomies and is characterized by ectopic location of the spleen within the abdomen or pelvis. It is always caused by excessive mobility brought on by the ligamentous laxity of its peritoneal attachments. Abdominal ultrasonography and computed tomography are the key imaging modalities for inquiry of WS. CASE PRESENTATION: We report the case of a 47-year-old woman who presented with painless abdominal swelling since the age of 6 years. An abdominal examination revealed a palpable, firm, mobile mass in the right lower abdomen approximately 15 × 15 cm in dimensions. A contrast CT scan of the abdomen revealed the absence of the spleen in the left upper quadrant. The patient was managed conservatively and followed for five years with favourable outcome. DISCUSSION: Failure of the dorsal mesogastrium to merge with the posterior abdominal wall in the second month of embryonic development is one of the reasons for WS. The nonsurgical conservative approach is limited to patients who are high-risk surgical candidates and have minimal symptoms and no complications. CONCLUSION: The good clinical outcome of our patient suggests that conservative non-surgical approach may be a reasonable alternative to unwarranted surgical intervention in selected clinically stable patients who have no evidence of splenic torsion or infarction, avoiding the possible complications of surgery.

Rational Design of Lipid-Based Vectors for Advanced Therapeutic Vaccines.

Recent advancements in vaccine delivery systems have seen the utilization of various materials, including lipids, polymers, peptides, metals, and inorganic substances, for constructing non-viral vectors. Among these, lipid-based nanoparticles, composed of natural, synthetic, or physiological lipid/phospholipid materials, offer significant advantages such as biocompatibility, biodegradability, and safety, making them ideal for vaccine delivery. These lipid-based vectors can protect encapsulated antigens and/or mRNA from degradation, precisely tune chemical and physical properties to mimic viruses, facilitate targeted delivery to specific immune cells, and enable efficient endosomal escape for robust immune activation. Notably, lipid-based vaccines, exemplified by those developed by BioNTech/Pfizer and Moderna against COVID-19, have gained approval for human use. This review highlights rational design strategies for vaccine delivery, emphasizing lymphoid organ targeting and effective endosomal escape. It also discusses the importance of rational formulation design and structure-activity relationships, along with reviewing components and potential applications of lipid-based vectors. Additionally, it addresses current challenges and future prospects in translating lipid-based vaccine therapies for cancer and infectious diseases into clinical practice.

mRNA vaccine designs for optimal adjuvanticity and delivery.

Adjuvanticity and delivery are crucial facets of mRNA vaccine design. In modern mRNA vaccines, adjuvant functions are integrated into mRNA vaccine nanoparticles, allowing the co-delivery of antigen mRNA and adjuvants in a unified, all-in-one formulation. In this formulation, many mRNA vaccines utilize the immunostimulating properties of mRNA and vaccine carrier components, including lipids and polymers, as adjuvants. However, careful design is necessary, as excessive adjuvanticity and activation of improper innate immune signalling can conversely hinder vaccination efficacy and trigger adverse effects. mRNA vaccines also require delivery systems to achieve antigen expression in antigen-presenting cells (APCs) within lymphoid organs. Some vaccines directly target APCs in the lymphoid organs, while others rely on APCs migration to the draining lymph nodes after taking up mRNA vaccines. This review explores the current mechanistic understanding of these processes and the ongoing efforts to improve vaccine safety and efficacy based on this understanding.

Lymphoma dissemination is a pathological hallmark for malignant progression of B-cell lymphoma.

Extranodal lymphoma occurs in one-third of lymphoma patients and is a key indicator of the international prognostic index, associated with unfavorable outcomes. Due to the lack of ideal models, the causes and characteristics of extranodal lymphoma are greatly underexplored. Recently, we observed a high incidence of extranodal lymphoma in two types of mouse models with tropism for the brain and kidneys. These findings prompt us to rethink the pathological progression of lymphoma colonization in lymph nodes and non-lymphoid organs. Nodal lymphoma, primary extranodal lymphoma and secondary extranodal lymphoma should be biologically and clinically distinctive scenarios. Based on the observations in mouse models with extranodal lymphoma, we propose that lymphoma dissemination can be seen as lymphoma losing the ability to home to lymph nodes. The pathological process of nodal lymphoma should be referred to as lymphoma homing to distinguish it from benign hyperplasia. Lymphoma dissemination, defined as a pathological process that lymphoma can occur in almost any part of the body, is a key pathological hallmark for malignant progression of B-cell lymphoma. Reshaping cellular plasticity is a promising strategy to allow transformed cells to homing back to lymph nodes and re-sensitize tumor cells to treatment. From this perspective, we provide new insights into the pathological progression of lymphoma dissemination and its inspiration on therapeutic interventions. We believe that establishing extranodal lymphoma mouse models, identifying molecular mechanism governing lymphoma dissemination, and developing therapies to prevent lymphoma dissemination will become emerging topics for fighting relapsed and refractory lymphoma.

Small Intestinal Adenocarcinoma Involving a Submucosal Ectopic Lymph Node: A Case Report.

An 83-year-old male with a 55-year history of Crohn's disease, ileocecectomy 40 years prior, and naturopathic treatment for 25 years, presented with nausea, vomiting, and abdominal pain. Computed tomography of abdomen and pelvis demonstrated partial small intestinal obstruction and a 4.4-cm solid left renal mass. After 3 months of recurrent intestinal obstruction and development of a pericolonic abscess, resection of the ileocolonic anastomosis, abscess, and partial nephrectomy were performed. Histopathology demonstrated chronic active enteritis with fistula tract formation, consistent with Crohn's disease, and moderately differentiated small intestinal adenocarcinoma extending from mucosa into subserosa. A submucosal intestinal lymph node-like structure containing adenocarcinoma demonstrated endothelial venules, open marginal and intermediate sinuses, multiple polarized germinal centers, and partial capsule, consistent with an ectopic lymph node, also called a tertiary lymphoid organ. Twenty mesenteric lymph nodes were negative for carcinoma. The renal mass was a papillary renal cell carcinoma, Stage I. Intestinal tertiary lymphoid organs form in chronic immune activation and have variable structures ranging from simple B and T cell clusters to organized groups with high endothelial venules and lymphatic vessels. Encapsulation of tertiary lymphoid organs is rare, with some sources claiming this entity is never encapsulated. To our knowledge, this is the first report of small intestinal adenocarcinoma involving a submucosal encapsulated tertiary lymphoid organ, the prognostic significance of which is uncertain. We suggest increased awareness of intestinal tertiary lymphoid organs as an entity and further studies to delineate the effect their involvement by adenocarcinoma imparts on survival.

Homeostatic role of B-1 cells in tissue immunity.

To date, studies of tissue-resident immunity have mainly focused on innate immune cells and T cells, with limited data on B cells. B-1 B cells are a unique subset of B cells with innate-like properties, enriched in murine pleural and peritoneal cavities and distinct from conventional B-2 cells in their ontogeny, phenotype and function. Here we discuss how B-1 cells represent exemplar tissue-resident immune cells, summarizing the evidence for their long-term persistence & self-renewal within tissues, differential transcriptional programming shaped by organ-specific environmental cues, as well as their tissue-homeostatic functions. Finally, we review the emerging data supporting the presence and homeostatic role of B-1 cells across non-lymphoid organs (NLOs) both in mouse and human.

Controversial role of ILC3s in intestinal diseases: A novelty perspective on immunotherapy.

ILC3s have been identified as crucial immune regulators that play a role in maintaining host homeostasis and modulating the antitumor response. Emerging evidence supports the idea that LTi cells play an important role in initiating lymphoid tissue development, while other ILC3s can promote host defense and orchestrate adaptive immunity, mainly through the secretion of specific cytokines and crosstalk with other immune cells or tissues. Additionally, dysregulation of ILC3-mediated overexpression of cytokines, changes in subset abundance, and conversion toward other ILC subsets are closely linked with the occurrence of tumors and inflammatory diseases. Regulation of ILC3 cytokines, ILC conversion and LTi-induced TLSs may be a novel strategy for treating tumors and intestinal or extraintestinal inflammatory diseases. Herein, we discuss the development of ILCs, the biology of ILC3s, ILC plasticity, the correlation of ILC3s and adaptive immunity, crosstalk with the intestinal microenvironment, controversial roles of ILC3s in intestinal diseases and potential applications for treatment.

Lymphoid tissue inducer cells in cancer: a potential therapeutic target.

Tumor cells are dynamic in nature; these cells first acquire immune surveillance and then escape from the immune system. Hence, progressed cancer cells distribute and metastasize to other organs via blood vessels as well as from the lymphatic system. Prognosis and treatment of metastatic cancer patients remain a major challenge nowadays. Till now, lots of target -based and immune checkpoint blocker therapies are used to treat disease patients. But these therapies fail to control the dissemination and metastasis of cancer. Before designing a treatment regimen for metastatic patients, understanding the mechanism of tumor cells spreading within lymph vessels remain undetermined. Construction of lymphoid structures since embryonic to adult stage are depend upon LTi. Foundation of lymph node, payer patches and TLO is initiated and regulated through these cells in any part of the body. During tumor growth, newly developed lymph node contained MDSCs and Treg cells which inhibit the immune response and promote tumor invasion and metastasis. LTi reconstituted lymph node can be used for both early and high risk detection of cancers. High and low risk of tumor growth and invasion depend upon the location and composition of immune cells within lymph nodes. However, LTi are not reported as predictive marker in cancer till date. Recent reports in cancer indicate that LTi cells are engaged in the spreading of tumor cells into a lymphatic vessel. Through this review we are trying to brief the development and role of the LTi in immune system during homeostasis and cancer.

Pathways linking aging and atheroprotection in Mif-deficient atherosclerotic mice.

Atherosclerosis is a chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. The pathogenesis is age-dependent, but the links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe-/- mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating leukocyte recruitment, lesional inflammation, and suppressing atheroprotective B cells. However, links between MIF and advanced atherosclerosis across aging have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe-/- mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week-old mice on a 6-week HFD. Mif-deficient mice exhibited reduced atherosclerotic lesions in the 30/24- and 42/36-week-old groups, but atheroprotection, which in the applied Apoe-/- model was limited to lesions in the brachiocephalic artery and abdominal aorta, was not detected in the 48/42- and 52/6-week-old groups. This suggested that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. To characterize this phenotype and study the underlying mechanisms, we determined immune cells in the periphery and vascular lesions, obtained a multiplex cytokine/chemokine profile, and compared the transcriptome between the age-related phenotypes. We found that Mif deficiency promotes lesional macrophage and T-cell counts in younger but not aged mice, with subgroup analysis pointing toward a role for Trem2+ macrophages. The transcriptomic analysis identified pronounced MIF- and aging-dependent changes in pathways predominantly related to lipid synthesis and metabolism, lipid storage, and brown fat cell differentiation, as well as immunity, and atherosclerosis-relevant enriched genes such as Plin1, Ldlr, Cpne7, or Il34, hinting toward effects on lesional lipids, foamy macrophages, and immune cells. Moreover, Mif-deficient aged mice exhibited a distinct plasma cytokine/chemokine signature consistent with the notion that mediators known to drive inflamm'aging are either not downregulated or even upregulated in Mif-deficient aged mice compared with the corresponding younger ones. Lastly, Mif deficiency favored formation of lymphocyte-rich peri-adventitial leukocyte clusters. While the causative contributions of these mechanistic pillars and their interplay will be subject to future scrutiny, our study suggests that atheroprotection due to global Mif-gene deficiency in atherogenic Apoe-/- mice is reduced upon advanced aging and identifies previously unrecognized cellular and molecular targets that could explain this phenotype shift. These observations enhance our understanding of inflamm'aging and MIF pathways in atherosclerosis and may have implications for translational MIF-directed strategies.

Murine neonatal dermal fibroblast acquires a lymphoid tissue organizer cell-like activity upon synergistic activation of TNF-α receptor and LTß receptor.

Tertiary lymphoid organs (TLOs) are ectopic aggregates of immune cells. As accumulating studies demonstrate TLOs as a predictor of better prognosis in certain cancers, targeting TLO formation, which is tightly regulated by the lymphoid tissue organizer cells (LTOs), has become intriguing in cancer treatment. However, the clinical outcome of these attempts is limited, because the approaches for activating tumor adjacent LTO is lack and little is known about what type of self-cell can be used as LTO to initiate TLO formation. Here we demonstrate that co-stimulation with membrane-bound ligand LTα1ß2 and soluble TNF-α could induced an LTO-like activity in murine neonatal dermal fibroblast, featured by high expression of cell migration-associated chemokines and adhesion molecules that resemble typical LTO gene signature. Furthermore, the LTO-phenotypic dermal fibroblast could enhance the attachment and survival of T and B cell and proliferation of T cell. These findings suggest dermal fibroblast as a promising target for TLO induction to improve cancer immunotherapy.

Severe gut mucosal injury induces profound systemic inflammation and spleen-associated lymphoid organ response.

Clinical evidence indicates a connection between gut injuries, infections, inflammation, and an increased susceptibility to systemic inflammation. Nevertheless, the animal models designed to replicate this progression are inadequate, and the fundamental mechanisms are still largely unknown. This research explores the relationship between gut injuries and systemic inflammation using a Dextran Sulfate Sodium (DSS)-induced colonic mucosal injury mouse model. Continuous treatment of adult mice with 4% DSS drinking water yielded a remarkable mortality rate by day 7, alongside intensified gut injury and detectable peripheral inflammation. Moreover, RNAscope in situ hybridization with 16S rRNA probe noted bacterial penetration into deeper colon compartments of the mice following treatment with DSS for 7 days. Histological analysis revealed inflammation in the liver and lung tissues of DSS-treated mice. In addition, we found that DSS-treated mice exhibited elevation of Alanine transaminase (ALT) and Aspartate transaminase (AST) in peripheral blood and pro-inflammatory cytokine levels in the liver. Notably, the DSS-treated mice displayed a dampened metabolic profile, reduced CD45 marker expression, and an increase in apoptosis within the lymphoid organ such as spleen. These findings suggest that high-dose DSS-induced gut injury gives rise to sepsis-like systemic inflammation characterized by multiple organ injury and profound splenocyte apoptosis and dysfunction of CD45+ cells in the spleen, indicating the role of the spleen in the pathogenesis of gut-derived systemic inflammation. Together, the severe colonic mucosal injury model facilitates research into gut damage and associated peripheral immune responses, providing a vital framework for investigating mechanisms related to clinically relevant, gut-derived systemic inflammation.

Regulation, Maintenance, and Remodeling of High Endothelial Venules in Homeostasis, Inflammation, and Cancer.

High endothelial venules (HEVs), high walled cuboidal blood vessels, through their expression of adhesion molecules and chemokines, allow the entrance of lymphoid cells into primary, secondary, and tertiary lymphoid structures (aka tertiary lymphoid organs). HEV heterogeneity exists between various lymphoid organs in their expression of peripheral node addressin (PNAd) and mucosal vascular addressin adhesion molecule 1(MAdCAM-1). Transcriptomic analyses reveal extensive heterogeneity, plasticity, and regulation of HEV gene expression in ontogeny, acute inflammation, and chronic inflammation within and between lymphoid organs. Rules regulating HEV development are flexible in inflammation. HEVs in tumor tertiary lymphoid structures are diagnostic of favorable clinical outcome and response to Immunotherapy, including immune check point blockade. Immunotherapy induces HEVs and provides an entrance for naïve, central memory, and effector cells and a niche for stem like precursor cells. Understanding HEV regulation will permit their exploitation as routes for drug delivery to autoimmune lesions, rejecting organs, and tumors.

Fully Attenuated meq and pp38 Double Gene Deletion Mutant Virus Confers Superior Immunological Protection against Highly Virulent Marek's Disease Virus Infection.

Marek's disease virus (MDV) induces immunosuppression and neoplastic disease in chickens. The virus is controllable via an attenuated meq deletion mutant virus, which has the disadvantage of retaining the ability to induce lymphoid organ atrophy. To overcome this deficiency and produce more vaccine candidates, a recombinant MDV was generated from the highly virulent Md5BAC strain, in which both meq and a cytolytic replication-related gene, pp38, were deleted. Replication of the double deletion virus, Md5BAC ΔmeqΔpp38, was comparable with that of the parental virus in vitro. The double deletion virus was shown to be fully attenuated and to reduce lymphoid organ atrophy in vivo. Crucially, Md5BAC ΔmeqΔpp38 confers superior protection against highly virulent virus compared with a commercial vaccine strain, CVI988/Rispens. Transcriptomic profiling indicated that Md5BAC ΔmeqΔpp38 induced a different host immune response from CVI988/Rispens. In summary, a novel, effective, and safe vaccine candidate for prevention and control of MD caused by highly virulent MDV is reported. IMPORTANCE MDV is a highly contagious immunosuppressive and neoplastic pathogen. The virus can be controlled through vaccination via an attenuated meq deletion mutant virus that retains the ability to induce lymphoid organ atrophy. In this study, we overcame the deficiency by generating meq and pp38 double deletion mutant virus. Indeed, the successfully generated meq and pp38 double deletion mutant virus had significantly reduced replication capacity in vivo but not in vitro. It was fully attenuated and conferred superior protection efficacy against very virulent MDV challenge. In addition, the possible immunological protective mechanism of the double deletion mutant virus was shown to be different from that of the gold standard MDV vaccine, CVI988/Rispens. Overall, we successfully generated an attenuated meq deletion mutant virus and widened the range of potential vaccine candidates. Importantly, this study provides for the first time the theoretical basis of vaccination induced by fully attenuated gene-deletion mutant virus.

Ultrastructure of cells constituting lymphoid tubules and circulating hemocytes in Penaeus monodon.

The two main groups of cells in the lymphoid tubule wall of Penaeus monodon are fixed cells and migrating hemocytes. Fixed cells include endothelial, stromal, and capsular cells. Together, they form the scaffold that defines the structure of the lymphoid tubule and provide physical support as well as a niche for transmigrating hemocytes. The luminal surface of lymphoid tubule was lined by elongated, spindle-shaped endothelial cells with a centrally located nucleus and rather thick plasma membrane. Stromal cells were the smallest type of fixed cell. They are stellate cells located between the inner endothelial and outer capsular cells. These cells formed a cyto-reticular network for migrating hemocytes. Capsular cells have a flattened and irregular shape with a ruffled border with long filamentous microvilli. The nucleus is centrally located within a small mass of cytoplasm. Together they form the outermost layer of the lymphoid tubular wall. Transmigrating hemocytes within the lymphoid tubules, as opposed to circulating hemocytes, were classified into hyaline (HH), small granular (SGH) and large granular (LGH) hemocytes. The HH have very few granules and a few cytoplasmic organelles, reflecting low synthetic activity. The granular hemocytes (SGH and LGH), despite being different in size, have similar ultrastructural characteristics. They contain high amounts of rough endoplasmic reticulum, ribosomes, mitochondria, and three types of granules. These characteristics implicate their higher synthetic as well as immunologic activities. Based on these characteristics we believe that all the hemocytes belong to a single line of cell differentiation.

Immunological imbalance in microcephalic children with congenital Zika virus syndrome.

Microcephalic children due congenital Zika virus syndrome (CZS) present neurological symptoms already well described. However, several other alterations can also be observed. Here, we aimed to evaluate the immune system of microcephaly CZS children. We showed that these patients have enlarged thymus, spleen and cervical lymph nodes, analysed by ultrasound and compared to the reference values for healthy children. In the periphery, they have an increase in eosinophil count and morphological alterations as hypersegmented neutrophils and atypical lymphocytes, even in the absence of urinary tract infections, parasitological infections or other current symptomatic infections. Microcephalic children due CZS also have high levels of IFN-γ, IL-2, IL-4, IL-5 and type I IFNs, compared to healthy controls. In addition, this population showed a deficient cellular immune memory as demonstrated by the low reactivity to the tuberculin skin test even though they had been vaccinated with BCG less than 2 years before the challenge with the PPD. Together, our data demonstrate for the first time that CZS can cause alterations in primary and secondary lymphoid organs and also alters the morphology and functionality of the immune system cells, which broadens the spectrum of CZS symptoms. This knowledge may assist the development of specific therapeutic and more efficient vaccination schemes for this population of patients.

Enhanced oxidative phosphorylation of IgG plasma cells can contribute to hypoxia in the mucosa of active ulcerative colitis.

Mucosal hypoxia is detected in the mucosa of ulcerative colitis (UC), however the mechanism and the cause of hypoxia is not fully understood, while a dense infiltration of plasma cells is observed in the inflamed mucosa of UC. When differentiating from a B cell to a plasma cell, the energy metabolism dramatically shifts from glycolysis to oxidative phosphorylation, which results in a large amount of oxygen consumption of the plasma cell. We hypothesized that the plasma cell infiltration into the inflamed mucosa contributes to the mucosal hypoxia in UC in part. We examined the association between mucosal hypoxia and plasma cell infiltration in UC. More IgG plasma cells (but not IgA plasma cells) were distributed, and the nuclear and cell sizes were enlarged in hypoxic mucosa compared to normoxic mucosa in UC. Oxidative phosphorylation signature genes of these IgG plasma cells were markedly upregulated compared to those of other lymphoid cells infiltrating the lamina propria of inflamed mucosa of UC. Enlarged IgG plasma cells, which increase in number in the inflamed mucosa of UC, can be related to the hypoxic state of the inflamed mucosa of UC.

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.