RESUMEN
CD4+Foxp3+ regulatory T cells (Tregs) are essential regulators of immune responses. Perturbation of Treg homeostasis or function can lead to uncontrolled inflammation and autoimmunity. Therefore, understanding the molecular mechanisms involved in Treg biology remains an active area of investigation. It has been shown previously that the NF-κB family of transcription factors, in particular, the canonical pathway subunits, c-Rel and p65, are crucial for the development, maintenance, and function of Tregs. However, the role of the alternative NF-κB pathway components, p100 and RelB, in Treg biology remains unclear. In this article, we show that conditional deletion of the p100 gene, nfkb2, in Tregs, resulted in massive inflammation because of impaired suppressive function of nfkb2-deficient Tregs. Surprisingly, mice lacking RelB in Tregs did not exhibit the same phenotype. Instead, deletion of both relb and nfkb2 rescued the inflammatory phenotype, demonstrating an essential role for p100 as an inhibitor of RelB in Tregs. Our data therefore illustrate a new role for the alternative NF-κB signaling pathway in Tregs that has implications for the understanding of molecular pathways driving tolerance and immunity.
Asunto(s)
Tolerancia Inmunológica/inmunología , Subunidad p52 de NF-kappa B/genética , Proteínas Nucleares/genética , Linfocitos T Reguladores/inmunología , Factor de Transcripción ReIB/genética , Animales , Autoinmunidad/inmunología , Diferenciación Celular , Células Cultivadas , Endonucleasas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subunidad p52 de NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas c-rel/metabolismo , Linfocitos T Reguladores/citología , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIB/metabolismoRESUMEN
Type I IFNs are critical players in host innate and adaptive immunity. IFN signaling is tightly controlled to ensure appropriate immune responses as imbalance could result in uncontrolled inflammation or inadequate responses to infection. It is therefore important to understand how type I IFN signaling is regulated. Here we have investigated the mechanism by which suppressor of cytokine signaling 1 (SOCS1) inhibits type I IFN signaling. We have found that SOCS1 inhibits type I IFN signaling not via a direct interaction with the IFN α receptor 1 (IFNAR1) receptor component but through an interaction with the IFNAR1-associated kinase Tyk2. We have characterized the residues/regions involved in the interaction between SOCS1 and Tyk2 and found that SOCS1 associates via its SH2 domain with conserved phosphotyrosines 1054 and 1055 of Tyk2. The kinase inhibitory region of SOCS1 is also essential for its interaction with Tyk2 and inhibition of IFN signaling. We also found that Tyk2 is preferentially Lys-63 polyubiquitinated and that this activation reaction is inhibited by SOCS1. The consequent effect of SOCS1 inhibition of Tyk2 not only results in a reduced IFN response because of inhibition of Tyk2 kinase-mediated STAT signaling but also negatively impacts IFNAR1 surface expression, which is stabilized by Tyk2.
Asunto(s)
Interferón Tipo I/metabolismo , Receptor de Interferón alfa y beta/metabolismo , Transducción de Señal/fisiología , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , TYK2 Quinasa/metabolismo , Animales , Estabilidad de Enzimas/fisiología , Regulación de la Expresión Génica/fisiología , Células HEK293 , Humanos , Interferón Tipo I/genética , Ratones , Ratones Noqueados , Receptor de Interferón alfa y beta/genética , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , TYK2 Quinasa/genética , Ubiquitinación/fisiología , Dominios Homologos srcRESUMEN
Inflammation plays a critical role in initiation of adaptive immunity, pathogen clearance and tissue repair. Interleukin (IL)-1ß is a potent pro-inflammatory cytokine and therefore its production is tightly regulated: its secretion requires the assembly of a macromolecular protein complex, termed the inflammasome. Aberrant activation of the inflammasome has been linked to debilitating human diseases including chronic inflammatory and autoimmune diseases. Thus, there is a great interest in understanding how inflammasomes are regulated. Here we show that Dicer, an enzyme necessary for the production of mature micro-RNAs (miRNAs), is required for optimal activation of NLRP3 inflammasomes in bone marrow macrophages. Our data indicate that miRNAs may play an important role in promoting inflammasome activation.
Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Inmunidad Innata/genética , Inflamasomas/inmunología , MicroARNs/metabolismo , Ribonucleasa III/metabolismo , Animales , Células Cultivadas , Biología Computacional , ARN Helicasas DEAD-box/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/inmunología , Inflamasomas/metabolismo , Macrófagos , Ratones , Ratones Transgénicos , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Cultivo Primario de Células , Ribonucleasa III/genética , Transducción de Señal/genética , Regulación hacia ArribaRESUMEN
After being delivered by the bite from an infected mosquito, Plasmodium sporozoites enter the blood circulation and infect the liver. Previous evidence suggests that Kupffer cells, a macrophage-like component of the liver blood vessel lining, are traversed by sporozoites to initiate liver invasion. However, the molecular determinants of sporozoite-Kupffer cell interactions are unknown. Understanding the molecular basis for this specific recognition may lead to novel therapeutic strategies to control malaria. Using a phage display library screen, we identified a peptide, P39, that strongly binds to the Kupffer cell surface and, importantly, inhibits sporozoite Kupffer cell entry. Furthermore, we determined that P39 binds to CD68, a putative receptor for sporozoite invasion of Kupffer cells that acts as a gateway for malaria infection of the liver.