RESUMEN
CD4+CD25+FoxP3+ cells (Tregs) inhibit inflammatory immune responses to allografts. Here, we found that co-transplantation of allogeneic pancreatic islets with Tregs that are defective in c-Jun N-terminal kinase 1 (JNK1) signaling prolongs islet allograft survival in the liver parenchyma of chemically induced diabetic mice (CDM). Adoptively transferred JNK1-/- but not wild-type (WT) Tregs survive longer in the liver parenchyma of CDM. JNK1-/- Tregs are resistant to apoptosis and express anti-apoptotic molecules. JNK1-/- Tregs express higher levels of lymphocyte activation gene-3 molecule (LAG-3) on their surface and produce higher amounts of the anti-inflammatory cytokine interleukin (IL)-10 compared with WT Tregs. JNK1-/- Tregs inhibit liver alloimmune responses more efficiently than WT Tregs. JNK1-/- but not WT Tregs are able to inhibit IL-17 and IL-21 production through enhanced LAG-3 expression and IL-10 production. Our study identifies a novel role of JNK1 signaling in Tregs that enhances islet allograft survival in the liver parenchyma of CDM.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Supervivencia de Injerto/inmunología , Proteína Quinasa 8 Activada por Mitógenos/genética , Tolerancia al Trasplante/inmunología , Aloinjertos/inmunología , Aloinjertos/trasplante , Animales , Antígenos CD/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/terapia , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/inmunología , Supervivencia de Injerto/genética , Humanos , Interleucina-17/genética , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Interleucinas/genética , Ratones , Ratones Endogámicos NOD , Proteína Quinasa 8 Activada por Mitógenos/inmunología , Linfocitos T Reguladores/inmunología , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
Pancreatic islet transplantation is a promising potential cure for type 1 diabetes (T1D). Islet allografts can survive long term in the liver parenchyma. Here we show that liver NK1.1+ cells induce allograft tolerance in a T1D mouse model. The tolerogenic effects of NK1.1+ cells are mediated through IL-22 production, which enhances allograft survival and increases insulin secretion. Increased expression of NKG2A by liver NK1.1+ cells in islet allograft-transplanted mice is involved in the production of IL-22 and in the reduced inflammatory response to allografts. Vaccination of T1D mice with a CpG oligonucleotide TLR9 agonist (ODN 1585) enhances expansion of IL-22-producing CD3-NK1.1+ cells in the liver and prolongs allograft survival. Our study identifies a role for liver NK1.1+ cells, IL-22 and CpG oligonucleotides in the induction of tolerance to islet allografts in the liver parenchyma.
Asunto(s)
Supervivencia de Injerto , Interleucinas/metabolismo , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/fisiología , Oligodesoxirribonucleótidos/inmunología , Receptor Toll-Like 9/agonistas , Animales , Islas de CpG , Diabetes Mellitus Tipo 1/cirugía , Ratones , Ratones Endogámicos NOD , Vacunación , Interleucina-22RESUMEN
In this study, we found that a subpopulation of CD4(+)CD25(+) (85% Foxp3(+)) cells from persons with latent tuberculosis infection (LTBI) inhibits growth of M. tuberculosis (M. tb) in human monocyte-derived macrophages (MDMs). A soluble factor, Rho GDP dissociation inhibitor (D4GDI), produced by apoptotic CD4(+)CD25(+) (85% Foxp3(+)) cells is responsible for this inhibition of M. tb growth in human macrophages and in mice. M. tb-expanded CD4(+C)D25(+)Foxp3(+)D4GDI(+) cells do not produce IL-10, TGF-ß and IFN-γ. D4GDI inhibited growth of M. tb in MDMs by enhancing production of IL-1ß, TNF-α and ROS, and by increasing apoptosis of M. tb-infected MDMs. D4GDI was concentrated at the site of disease in tuberculosis patients, with higher levels detected in pleural fluid than in serum. However, in response to M. tb, PBMC from tuberculosis patients produced less D4GDI than PBMC from persons with LTBI. M. tb-expanded CD4+CD25+ (85% Foxp3(+)) cells and D4GDI induced intracellular M. tb to express the dormancy survival regulator DosR and DosR-dependent genes, suggesting that D4GDI induces a non-replicating state in the pathogen. Our study provides the first evidence that a subpopulation of CD4(+)CD25(+) (85% Foxp3+) cells enhances immunity to M. tb, and that production of D4GDI by this subpopulation inhibits M. tb growth.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Tuberculosis Latente/inmunología , Macrófagos/microbiología , Subgrupos de Linfocitos T/inmunología , Inhibidores de la Disociación del Nucleótido Guanina rho-Específico/inmunología , Adolescente , Adulto , Anciano , Animales , Apoptosis/inmunología , Separación Celular , Técnicas de Cocultivo , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Persona de Mediana Edad , Mycobacterium tuberculosis , Reacción en Cadena en Tiempo Real de la Polimerasa , Tuberculosis/inmunología , Adulto JovenRESUMEN
Innate immune system is crucial in the pathogenesis of neurocysticercosis (NCC) and helminth glycans can induce anti-inflammatory milieu via toll-like receptor 4 (TLR4) dependent mechanisms. The association of TLR4 and cytokines is yet to be explored in NCC. Therefore, the present study detected the serum levels of cytokines and soluble intercellular adhesion molecule (sICAM)-1 in asymptomatic and symptomatic NCC and their association with TLR4 expression. Sixty eight patients with NCC (asymptomatic, 36 and symptomatic, 32), and age and gender matched 37 healthy controls were enrolled to determine the levels of different pro- and anti-inflammatory cytokines, sICAM-1 in the serum by ELISA and expression of TLR4 in peripheral blood mononuclear cells (PBMCs) by flow cytometry. In asymptomatic NCC cases, the levels of IL-10 and IL-4 were significantly elevated compared to healthy controls and symptomatic NCC patients whereas the levels of IFN-γ, TNF-α, IL-17, IL-23 and sICAM-1 were higher in symptomatic NCC patients compared to healthy controls and asymptomatic NCC individuals. Frequency of TLR4 expressing PBMCs and CD14 positive cells were significantly higher in both groups of NCC. Although the number of TLR4 expressing cells was almost similar in both asymptomatic and symptomatic groups, the median fluorescence intensity was significantly higher in symptomatic group indicating that higher levels of TLR4 expression in symptomatic patients correlated with enhanced pro-inflammatory cytokine production.