RESUMEN
Group 2 innate lymphoid cells (ILC2s) are crucial in promoting type 2 inflammation that contributes to both anti-parasite immunity and allergic diseases. However, the molecular checkpoints in ILC2s that determine whether to immediately launch a proinflammatory response are unknown. Here, we found that retinoid X receptor gamma (Rxrg) was highly expressed in small intestinal ILC2s and rapidly suppressed by alarmin cytokines. Genetic deletion of Rxrg did not impact ILC2 development but facilitated ILC2 responses and the tissue inflammation induced by alarmins. Mechanistically, RXRγ maintained the expression of its target genes that support intracellular cholesterol efflux, which in turn reduce ILC2 proliferation. Furthermore, RXRγ expression prevented ILC2 response to mild stimulations, including low doses of alarmin cytokine and mechanical skin injury. Together, we propose that RXRγ expression and its mediated lipid metabolic states function as a cell-intrinsic checkpoint that confers the threshold of ILC2 activation in the small intestine.
Asunto(s)
Inmunidad Innata , Receptor gamma X Retinoide , Humanos , Alarminas , Linfocitos , Inflamación , Citocinas/metabolismo , Intestino Delgado/metabolismoRESUMEN
Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.
Asunto(s)
Inmunidad Innata , Neumonía , Humanos , Dopamina/metabolismo , Linfocitos , Pulmón/metabolismo , Neumonía/metabolismo , Inflamación/metabolismo , Interleucina-33/metabolismoRESUMEN
Ever-growing evidence has revealed that group 2 innate lymphoid cells (ILC2s) exhibit pleiotropic effects in antihelminth immunity, allergy, tissue protection, and cancer. Currently, the role of ILC2s in cancer is highly controversial regarding the intricate tumor microenvironment (TME), and the tumor-promoting or antitumor immunological mechanisms of ILC2s remain largely unknown. In this study, we report that dopamine receptor 1 (DRD1) restrains ILC2 activity in the TME. DRD1 deficiency promotes ILC2 activation, which irritates eosinophil recruitment and cytotoxic CD8+ T cell expansion during ongoing malignancy. Consequently, DRD1-deficient mice exhibit delayed tumor growth and reduced tumor progression. Furthermore, fenoldopam, a selective DRD1 agonist, restrains the ILC2 response in the TME and aggravates tumor burden in mice. Taken together, our data elaborate that the DRD1 signal acts as an excitatory rheostat in regulating ILC2-dependent antitumor immunity.
RESUMEN
Group 2 innate lymphoid cells (ILC2s) play an important role in the control of tissue inflammation and homeostasis. However, the role of ILC2s in patients with end-stage renal disease (ESRD) has never been illustrated. In this study, we investigated ILC2s in ESRD patients and their clinical significance. Results showed that the frequencies and absolute numbers of ILC2s, not group 1 innate lymphoid cells or innate lymphoid cell precursors, were significantly elevated in the peripheral blood of ESRD patients when compared with those from healthy donor controls. Moreover, ILC2s from ESRD patients displayed enhanced type 2 cytokine production and cell proliferation. Plasma from ESRD patients significantly increased ILC2 levels and enhanced their effector function after in vitro treatment. The expression of phosphorylation of STAT5 in ILC2s, as well as the amounts of IL-2 in plasma, were increased in ESRD patients when compared with those from healthy donors. Clinically, ESRD patients with higher ILC2 frequencies displayed lower incidence of infectious complications during a mean of 21 month follow-up study. The proportions of ILC2s were negatively correlated with the prognostic biomarkers of chronic kidney disease, including serum parathyroid hormone, creatinine, and phosphorus, whereas they were positively correlated with serum calcium. These observations indicate that ILC2s may play a protective role in ESRD.
Asunto(s)
Inmunidad Innata , Fallo Renal Crónico/inmunología , Subgrupos Linfocitarios/inmunología , Adulto , Animales , Biomarcadores/sangre , Estudios de Casos y Controles , Proliferación Celular , Células Cultivadas , Citocinas/metabolismo , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Voluntarios Sanos , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Recuento de Linfocitos , Subgrupos Linfocitarios/metabolismo , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Pronóstico , Diálisis Renal/estadística & datos numéricosRESUMEN
Secretory Ig A (sIgA) plays an important role in the maintenance of intestinal homeostasis via cross-talk with gut microbiota. The defects in sIgA production could elicit dysbiosis of commensal microbiota and subsequently facilitate the development of inflammatory bowel disease. Our previous study revealed activating transcription factor 3 (ATF3) as an important regulator of follicular helper T (TFH) cells in gut. ATF3 deficiency in CD4+ T cells impaired the development of gut TFH cells, and therefore diminished sIgA production, which increased the susceptibility to murine colitis. However, the potential role of microbiota in ATF3-mediated gut homeostasis remains incompletely understood. In this study, we report that both Atf3-/- and CD4creAtf3fl/fl mice displayed profound dysbiosis of gut microbiota when compared with their littermate controls. The proinflammatory Prevotella taxa, especially Prevotella copri, were more abundant in ATF3-deficient mice when compared with littermate controls. This phenotype was obviously abrogated by adoptive transfer of either TFH cells or IgA+ B cells. Importantly, depletion of gut microbiota dramatically alleviated the severity of colitis in Atf3-/- mice, whereas transfer of microbiota from Atf3-/- mice to wild-type recipients increased their susceptibility to colitis. Collectively, these observations indicate the importance of IgA-microbiota interaction in ATF3-mediated gut homeostasis.
Asunto(s)
Factor de Transcripción Activador 3/inmunología , Linfocitos B/inmunología , Microbioma Gastrointestinal/inmunología , Homeostasis/inmunología , Inmunoglobulina A/inmunología , Células T Auxiliares Foliculares/inmunología , Factor de Transcripción Activador 3/genética , Animales , Disbiosis/genética , Disbiosis/inmunología , Disbiosis/microbiología , Homeostasis/genética , Inmunoglobulina A/genética , Ratones , Ratones Noqueados , Prevotella/inmunologíaRESUMEN
Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (TFH) cells in the gut. The expression of ATF3 in CD4+ T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4+ T cells (CD4creAtf3fl/fl ) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of TFH cells, not other T cell subsets, were dramatically decreased in Peyer's patches from CD4creAtf3fl/fl mice compared with Atf3fl/fl littermate controls. The defective TFH cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of TFH or IgA+ B cells caused significant remission of colitis in CD4creAtf3fl/fl mice, indicating the TFH-IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4+ T cells. In summary, we demonstrated ATF3 as a regulator of TFH cells in the gut, which may represent a potential immunotherapeutic target in colitis.
Asunto(s)
Factor de Transcripción Activador 3/inmunología , Factor de Transcripción Activador 3/farmacología , Colitis/tratamiento farmacológico , Colitis/inmunología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Traslado Adoptivo , Animales , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Colitis/patología , Colitis Ulcerosa , Colon/patología , Sulfato de Dextran/efectos adversos , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Homeostasis , Inmunidad Mucosa/inmunología , Inmunoglobulina A , Inmunoterapia , Ratones , Ganglios Linfáticos Agregados/inmunología , Subgrupos de Linfocitos TRESUMEN
Cyclooxygenase (COX)-1, one of the critical enzymes required for the conversion of arachidonic acid to PGs, has been demonstrated to play an important role not only in the cardiovascular system but also in the immune system. COX-1 has been found to regulate early B cell differentiation, germinal center formation, and Ab production of B cells. However, the underlying mechanisms of COX-1-mediated B cell activation remains not fully understood. In this study, we reported that COX-1 is a potential regulator for the development of follicular Th (TFH) cells. COX-1-deficient (COX-1-/- ) mice displayed a significant reduction of TFH cells upon influenza infection or immunization with keyhole limpet hemocyanin, which led to a severe impairment of germinal center responses. We further demonstrated that COX-1-derived PGE2, via binding with its receptors EP2/EP4, represents the underlying mechanism. The administration of EP2/EP4 agonists or PGE2 almost completely rescued the defective TFH cell generation in COX-1-/- mice. Taken together, our observations indicate that COX-1 plays an important role in the development of TFH cells.
Asunto(s)
Ciclooxigenasa 1/inmunología , Dinoprostona/inmunología , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular/inmunología , Centro Germinal/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
Hyperactivation of the type 2 immune response is the major mechanism of allergic asthma, in which both group 2 innate lymphoid cells (ILC2s) and type 2 helper T (Th2) cells participate. Myeloid-derived suppressor cells (MDSCs) alleviate asthma by suppressing Th2 cells. However, the potential effects of MDSCs on the biological functions of ILC2s remain largely unknown. Here, we examined the roles of MDSCs (MDSCs) in the modulation of ILC2 function. Our results showed that polymorphonuclear (PMN)-MDSCs, but not monocytic (M-) MDSCs, effectively suppressed the cytokine production of ILC2s both in vitro and in vivo, thereby alleviating airway inflammation. Further analyses showed that cyclo-oxygenase-1 may mediate the suppressive effects of PMN-MDSCs on ILC2 responses. Our findings demonstrated that PMN-MDSCs may serve as a potent therapeutic target for the treatment of ILC2-driven allergic asthma.
Asunto(s)
Alérgenos/inmunología , Asma/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Linfocitos/inmunología , Células Supresoras de Origen Mieloide/inmunología , Sistema Respiratorio/inmunología , Animales , Asma/patología , Movimiento Celular/inmunología , Células Cultivadas , Citocinas/biosíntesis , Citocinas/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Humanos , Inflamación/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Statins, widely prescribed as cholesterol-lowering drugs, have recently been extensively studied for their pleiotropic effects on immune systems, especially their beneficial effects on autoimmune and inflammatory disorders. However, the mechanism of statin-induced immunosuppression is far from understood. Here, we found that atorvastatin promoted the expansion of myeloid-derived suppressor cells (MDSCs) both in vitro and in vivo. Atorvastatin-derived MDSCs suppressed T-cell responses by nitric oxide production. Addition of mevalonate, a downstream metabolite of 3-hydroxy-3-methylglutaryl coenzyme A reductase, almost completely abrogated the effect of atorvastatin on MDSCs, indicating that the mevalonate pathway was involved. Along with the amelioration of dextran sodium sulphate (DSS) -induced murine acute and chronic colitis, we observed a higher MDSC level both in spleen and intestine tissue compared with that from DSS control mice. More importantly, transfer of atorvastatin-derived MDSCs attenuated DSS acute colitis and T-cell transfer of chronic colitis. Hence, our data suggest that the expansion of MDSCs induced by statins may exert a beneficial effect on autoimmune diseases. In summary, our study provides a novel potential mechanism for statins-based treatment in inflammatory bowel disease and perhaps other autoimmune diseases.
Asunto(s)
Antiinflamatorios/uso terapéutico , Atorvastatina/uso terapéutico , Colitis/tratamiento farmacológico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Linfocitos T/inmunología , Animales , Células Cultivadas , Colitis/inducido químicamente , Sulfato de Dextran , Humanos , Terapia de Inmunosupresión , Ácido Mevalónico/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Células Supresoras de Origen Mieloide/fisiología , Óxido Nítrico/metabolismoRESUMEN
Cyclooxygenases (COXs) and their prostanoid products play important roles in a diverse range of physiological processes, including in the immune system. Here, we provide evidence that COX-1 is an essential regulator in early stages of B-cell development. COX-1-deficient mice displayed systematic reduction in total B cells, which was attributed to the arrest of early B-cell development from pro-B to pre-B stage. We further demonstrated that this defect was mediated through downregulation of the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling and its target genes, including Pax5, in COX-1(-/-) mice. Mechanistic studies revealed that COX-1-derived thromboxane A2 (TxA2) could regulate JAK3/STAT5 signaling through the cyclic adenosine monophosphate-protein kinase A pathway, via binding with its receptor thromboxane A2 receptor (TP). Administration of the TP agonist could rescue the defective B-cell development and JAK/STAT5 signaling activity in COX-1-deficient mice. Moreover, administration of low-dose aspirin caused a significant reduction in total B cells in peripheral blood of healthy human volunteers, coincidentally with reduced TxA2 production and downregulation of JAK/STAT5 signaling. Taken together, our results demonstrate that COX-1-derived TxA2 plays a critical role in the stage transition of early B-cell development through regulation of JAK/STAT5 signaling and indicate a potential immune-suppressive effect of low-dose aspirin in humans.
Asunto(s)
Linfocitos B/fisiología , Diferenciación Celular , Ciclooxigenasa 1/metabolismo , Proteínas de la Membrana/metabolismo , Tromboxano A2/fisiología , Animales , Diferenciación Celular/genética , Células Cultivadas , Ciclooxigenasa 1/genética , Humanos , Quinasas Janus/metabolismo , Leucopoyesis/genética , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/genética , Tromboxano A2/metabolismoRESUMEN
The transitory emergence of myeloid-derived suppressor cells (MDSCs) in infants is important for the homeostasis of the immune system in early life. The composition and functional heterogeneity of MDSCs in newborns remain elusive, hampering the understanding of the importance of MDSCs in neonates. In this study, we unraveled the maturation trajectory of polymorphonuclear (PMN)-MDSCs from the peripheral blood of human newborns by performing single-cell RNA sequencing. Results indicated that neonatal PMN-MDSCs differentiated from self-renewal progenitors, antimicrobial PMN-MDSCs, and immunosuppressive PMN-MDSCs to late PMN-MDSCs with reduced antimicrobial capacity. We also established a simple framework to distinguish these distinct stages by CD177 and CXCR2. Importantly, preterm newborns displayed a reduced abundance of classical PMN-MDSCs but increased late PMN-MDSCs, consistent with their higher susceptibility to infections and inflammation. Furthermore, newborn PMN-MDSCs were distinct from those from cancer patients, which displayed minimum expression of genes about antimicrobial capacity. This study indicates that the heterogeneity of PMN-MDSCs is associated with the maturity of human newborns.
Asunto(s)
Perfilación de la Expresión Génica , Células Supresoras de Origen Mieloide , Receptores de Interleucina-8B , Análisis de la Célula Individual , Transcriptoma , Humanos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Recién Nacido , Receptores de Interleucina-8B/metabolismo , Receptores de Interleucina-8B/genética , Neutrófilos/inmunología , Neutrófilos/metabolismo , Proteínas Ligadas a GPI/genética , Diferenciación Celular , Femenino , Masculino , Isoantígenos , Receptores de Superficie CelularRESUMEN
Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination.
Asunto(s)
Epítopos de Linfocito T , Inmunoterapia , Neoplasias , Virus Oncolíticos , SARS-CoV-2 , Microambiente Tumoral , Humanos , Animales , Ratones , Virus Oncolíticos/inmunología , Inmunoterapia/métodos , Epítopos de Linfocito T/inmunología , Microambiente Tumoral/inmunología , SARS-CoV-2/inmunología , Neoplasias/terapia , Neoplasias/inmunología , Viroterapia Oncolítica/métodos , Línea Celular Tumoral , COVID-19/inmunología , COVID-19/terapia , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Antígenos de Neoplasias/inmunología , Linfocitos T/inmunologíaRESUMEN
The COVID-19 vaccinations are crucial in protecting against the global pandemic. However, accumulating studies revealed the severely blunted COVID-19 vaccine effectiveness in cancer patients. The PD-1/PD-L1 immune checkpoint blockade (ICB) therapy leads to durable therapeutic responses in a subset of cancer patients and has been approved to treat a wide spectrum of cancers in the clinic. In this regard, it is pivotal to explore the potential impact of PD-1/PD-L1 ICB therapy on COVID-19 vaccine effectiveness during ongoing malignancy. In this study, using preclinical models, we found that the tumor-suppressed COVID-19 vaccine responses are largely reverted in the setting of PD-1/PD-L1 ICB therapy. We also identified that the PD-1/PD-L1 blockade-directed restoration of COVID-19 vaccine effectiveness is irrelevant to anti-tumor therapeutic outcomes. Mechanistically, the restored COVID-19 vaccine effectiveness is entwined with the PD-1/PD-L1 blockade-driven preponderance of follicular helper T cell and germinal center responses during ongoing malignancy. Thus, our findings indicate that PD-1/PD-L1 blockade will greatly normalize the responses of cancer patients to COVID-19 vaccination, while regardless of its anti-tumor efficacies on these patients.
Asunto(s)
COVID-19 , Neoplasias , Humanos , Vacunas contra la COVID-19 , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Antígeno B7-H1 , Receptor de Muerte Celular Programada 1 , COVID-19/prevención & control , Neoplasias/terapia , InmunoterapiaRESUMEN
Transitory appearance of immune suppressive polymorphonuclear neutrophils (PMNs) defined as myeloid-derived suppressor cells (PMNs-MDSCs) in newborns is important for their protection from inflammation associated with newly established gut microbiota. Here, we report that inhibition of the type I IFN (IFN1) pathway played a major role in regulation of PMNs-MDSCs-suppressive activity during first weeks of life. Expression of the IFN1 receptor IFNAR1 was markedly lower in PMNs-MDSCs. However, in newborn mice, down-regulation of IFNAR1 was not sufficient to render PMNs immune suppressive. That also required the presence of a positive signal from lactoferrin via its receptor low-density lipoprotein receptor-related protein 2. The latter effect was mediated via NF-κB activation, which was tempered by IFN1 in a manner that involved suppressor of cytokine signaling 3. Thus, we discovered a mechanism of tight regulation of immune suppressive PMNs-MDSCs in newborns, which may be used in the development of therapies of neonatal pathologies.
Asunto(s)
Células Supresoras de Origen Mieloide , Ratones , Animales , Neutrófilos , Lactoferrina/metabolismo , FN-kappa B/metabolismo , Citocinas/metabolismo , Lipoproteínas LDL/metabolismoRESUMEN
Group 2 innate lymphoid cells (ILC2s) have emerged as critical mediators in driving allergic airway inflammation. Here, we identified angiotensin (Ang) II as a positive regulator of ILC2s. ILC2s expressed higher levels of the Ang II receptor AT1a, and colocalized with lung epithelial cells expressing angiotensinogen. Administration of Ang II significantly enhanced ILC2 responses both in vivo and in vitro, which were almost completely abrogated in AT1a-deficient mice. Deletion of AT1a or pharmacological inhibition of the Ang II-AT1 axis resulted in a remarkable remission of airway inflammation. The regulation of ILC2s by Ang II was cell intrinsic and dependent on interleukin (IL)-33, and was associated with marked changes in transcriptional profiling and up-regulation of ERK1/2 phosphorylation. Furthermore, higher levels of plasma Ang II correlated positively with the abundance of circulating ILC2s as well as disease severity in asthmatic patients. These observations reveal a critical role for Ang II in regulating ILC2 responses and airway inflammation.
Asunto(s)
Angiotensina II/metabolismo , Inmunidad Innata , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Enfermedades Respiratorias/etiología , Enfermedades Respiratorias/metabolismo , Animales , Biomarcadores , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/metabolismo , Hiperreactividad Bronquial/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inflamación , Interleucina-33/metabolismo , Ratones , Ratones Noqueados , Receptor de Angiotensina Tipo 1/genética , Enfermedades Respiratorias/patologíaRESUMEN
BACKGROUND: Regulatory B (Breg) cells represent one of the B cell subsets that infiltrate solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the phenotype, function and clinical relevance of Breg cells in human hepatocellular carcinoma (HCC) are presently unknown. METHODS: Flow cytometry analyses were performed to determine the levels, phenotypes and functions of TIM-1+Breg cells in samples from 51 patients with HCC. Kaplan-Meier plots for overall survival and disease-free survival were generated using the log-rank test. TIM-1+Breg cells and CD8+ T cells were isolated, stimulated and/or cultured in vitro for functional assays. Exosomes and B cells were isolated and cultured in vitro for TIM-1+Breg cell expansion assays. RESULTS: Patients with HCC showed a significantly higher TIM-1+Breg cell infiltration in their tumor tissue compared with the paired peritumoral tissue. The infiltrating TIM-1+Breg cells showed a CD5highCD24-CD27-/+CD38+/high phenotype, expressed high levels of the immunosuppressive cytokine IL-10 and exhibited strong suppressive activity against CD8+ T cells. B cells activated by tumor-derived exosomes strongly expressed TIM-1 protein and were equipped with suppressive activity against CD8+ T cells similar to TIM-1+Breg cells isolated from HCC tumor tissue. Moreover, the accumulation of TIM-1+Breg cells in tumors was associated with advanced disease stage, predicted early recurrence in HCC and reduced HCC patient survival. Exosome-derived HMGB1 activated B cells and promoted TIM-1+Breg cell expansion via the Toll like receptor (TLR) 2/4 and mitogen-activated protein kinase (MAPK) signaling pathways. CONCLUSIONS: Our results illuminate a novel mechanism of TIM-1+Breg cell-mediated immune escape in HCC and provide functional evidence for the use of these novel exosomal HMGB1-TLR2/4-MAPK pathways to prevent and to treat this immune tolerance feature of HCC.