RESUMEN
Von Hippel-Lindau (VHL) is an E3 ubiquitin ligase that targets proteins, including HIF-1α, for proteasomal degradation. VHL and HIF regulate the balance between glycolysis and oxidative phosphorylation, which is critical in highly dynamic T cells. HIF-1α positively regulates Th17 differentiation, a complex process in which quiescent naive CD4 T cells undergo transcriptional changes to effector cells, which are commonly dysregulated in autoimmune diseases. The role of VHL in Th17 cells is not known. In this study, we hypothesized VHL negatively regulates Th17 differentiation and deletion of VHL in CD4 T cells would elevate HIF-1α and increase Th17 differentiation. Unexpectedly, we found that VHL promotes Th17 differentiation. Mice deficient in VHL in their T cells were resistant to an autoimmune disease, experimental autoimmune encephalomyelitis, often mediated by Th17 cells. In vitro Th17 differentiation was impaired in VHL-deficient T cells. In the absence of VHL, Th17 cells had decreased activation of STAT3 and SMAD2, suggesting that VHL indirectly or directly regulates these critical signaling molecules. Gene expression analysis revealed that in Th17 cells, VHL regulates many cellular pathways, including genes encoding proteins involved indirectly or directly in the glycolysis pathway. Compared with wild-type, VHL-deficient Th17 cells had elevated glycolysis and glycolytic capacity. Our finding has implications on the design of therapeutics targeting the distinct metabolic needs of T cells to combat chronic inflammatory diseases.
Asunto(s)
Diferenciación Celular/fisiología , Células Th17/metabolismo , Células Th17/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Animales , Femenino , Expresión Génica/fisiología , Glucólisis/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/fisiología , Proteína Smad2/metabolismoRESUMEN
IL-22 is expressed by activated lymphocytes and is important in modulation of tissue responses during inflammation. The cytokine induces proliferative and antiapoptotic pathways in epithelial cells allowing enhanced cell survival. This can have positive effects, such as in the maintenance of epithelial barriers in the gastrointestinal tract, but also negative effects, such as contributing to colorectal tumorigenesis. Because IL-22 can be dual-natured, we hypothesized that its biological activity should be tightly regulated to limit IL-22 expression to the sites of inflammation. One such environmental cue could be low oxygen, which often accompanies inflammation. We show that in CD4 T cells IL-22 expression is upregulated in hypoxia. The Il22 promoter contains a putative conserved hypoxic response element suggesting that the transcription factor HIF-1α may influence IL-22 expression. Differentiation in the presence of dimethyloxallyl glycine, a stabilizer of HIF-1α at normoxia, increased IL-22 expression. Using HIF-1α-deficient CD4 T cells, we show that hypoxic IL-22 upregulation is dependent on HIF-1α. These findings have implications on the regulation of Il22 gene expression and the presence of the cytokine in different inflammatory environments.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interleucinas/genética , Animales , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Células Cultivadas , Hipoxia/inmunología , Interleucinas/biosíntesis , Interleucinas/inmunología , Ratones , Ratones Endogámicos C57BL , Oxígeno/inmunología , Interleucina-22Asunto(s)
Antígenos CD5/metabolismo , Regulación de la Expresión Génica , Linfocitos T Reguladores/citología , Antígenos/inmunología , Antígenos/metabolismo , Autoinmunidad , Diferenciación Celular , Humanos , Sistema Inmunológico , Inflamación , Receptores de Antígenos de Linfocitos T/metabolismo , Timo/citologíaRESUMEN
Dendritic cells (DCs) can induce peripheral immune tolerance that prevents autoimmune responses. Ag presentation by peripheral DCs under steady-state conditions leads to a conversion of some peripheral CD4(+) T cells into regulatory T cells (Tregs) that require homeodomain-only protein (Hopx) to mediate T cell unresponsiveness. However, the roles of these peripheral Tregs (pTregs) in averting autoimmune responses, as well as immunological mechanisms of Hopx, remain unknown. We report that Hopx(+) pTregs converted by DCs from Hopx(-) T cells are indispensible to sustain tolerance that prevents autoimmune responses directed at self-Ags during experimental acute encephalomyelitis. Our studies further reveal that Hopx inhibits intrinsic IL-2 expression in pTregs after antigenic rechallenge. In the absence of Hopx, increased levels of IL-2 lead to death and decreased numbers of pTregs. Therefore, formation of Hopx(+) pTregs represents a crucial pathway of sustained tolerance induced by peripheral DCs, and the maintenance of such pTregs and tolerance requires functions of Hopx to block intrinsic IL-2 production in pTregs.
Asunto(s)
Regulación de la Expresión Génica , Proteínas de Homeodominio/genética , Tolerancia Inmunológica/genética , Interleucina-2/genética , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Autoantígenos/inmunología , Autoinmunidad/genética , Autoinmunidad/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Inflamación/genética , Inflamación/inmunología , Inflamación/metabolismo , Ratones , Ratones NoqueadosRESUMEN
Self-reactive T cells can escape thymic deletion and therefore some of these potentially autoaggressive T cells need to convert into regulatory T (Treg) cells to help control responses against self. However, it remains unknown how peripheral self-reactive T cells are specifically instructed to become Treg cells. We report that CD5, whose expression is upregulated in T cells by self and tolerizing antigens in the thymus and periphery, governed extrathymic Treg cell development. CD5 modified effector cell-differentiating signals that inhibit Treg cell induction. Treg cell conversion of Cd5(-/-) and CD5(lo) T cells was inhibited by even small amounts of interleukin-4 (IL-4), IL-6, and interferon-γ (IFN-γ) produced by bystander lymphocytes, while CD5(hi) T cells resisted this inhibition of Treg cell induction. Our findings further revealed that CD5 promoted Treg cell induction by blocking mechanistic target of rapamycin (mTOR) activation. Therefore CD5 instructs extrathymic Treg cell development in response to self and tolerizing antigens.
Asunto(s)
Autoantígenos/inmunología , Antígenos CD5/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Autoantígenos/genética , Efecto Espectador/inmunología , Antígenos CD5/genética , Diferenciación Celular , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Regulación de la Expresión Génica , Interferón gamma/genética , Interferón gamma/inmunología , Interferón gamma/farmacología , Interleucina-4/genética , Interleucina-4/inmunología , Interleucina-4/farmacología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucina-6/farmacología , Ratones , Ratones Noqueados , Tolerancia Periférica , Transducción de Señal , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/inmunología , Timo/citología , Timo/inmunologíaRESUMEN
Multiple sclerosis (MS) is a presumed autoimmune disease directed against central nervous system (CNS) myelin, in which diet and obesity are implicated as risk factors. Immune responses can be influenced by molecules produced by fat cells, called adipokines. Adiponectin is an adipokine with anti-inflammatory effects. We tested the hypothesis that adiponectin has a protective role in the EAE model for MS, that can be induced by immunization with myelin antigens or transfer of myelin-specific T lymphocytes. Adiponectin deficient (ADPKO) mice developed worse EAE with greater CNS inflammation, demyelination, and axon injury. Lymphocytes from myelin-immunized ADPKO mice proliferated more, produced higher amounts of IFN-γ, IL-17, TNF-α, IL-6, and transferred more severe EAE than wild type (WT) lymphocytes. At EAE peak, the spleen and CNS of ADPKO had fewer regulatory T (Treg) cells than WT mice and during EAE recovery, Foxp3, IL-10 and TGF-ß expression levels in the CNS were reduced in ADPKO compared with WT mice. Treatment with globular adiponectin in vivo ameliorated EAE, and was associated with an increase in Treg cells. These data indicate that adiponectin is an important regulator of T-cell functions during EAE, suggesting a new avenue of investigation for MS treatment.