ISG15 at crossroads of immune synapse, dendritic cells and contact hypersensitivity
Author
Fernández Delgado, IreneAdvisor
Sánchez Madrid, FranciscoEntity
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC); Hospital Universitario de La PrincesaDate
2022-05-27Funded by
I.F.D was supported by a Fellowship from Spanish Ministry of Science, Innovation and Universities (FPU15/02539). This work was supported by: ◦ Grant SAF2014-55579-R from the Spanish Ministry of Economy and Competitiveness (MINECO) ◦ Grant SAF2017-82886-R from the Spanish Ministry of Economy and Competitiveness (MINECO) ◦ Grant from the Ramón Areces Foundation “Ciencias de la Vida y la Salud” (XIX Concurso-2018) ◦ “La Caixa” Banking Foundation (HR17-00016). ◦ CIBER Cardiovascular (CB16/11/00272, Fondo de Investigación Sanitaria del Instituto de Salud Carlos III and co-funding by Fondo Europeo de Desarrollo Regional FEDER). ◦ Grant PDI-2020-120412RB-I00 from the Spanish Ministry of Economy and Competitiveness (MINECO) The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). Funding agencies do not have intervened in the design of the studies, with no copyright over the studySubjects
Biociencias Moleculares; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 27-05-2022Esta Tesis tiene embargado el acceso al texto completo hasta el 27-11-2023
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Understanding the fate of dendritic cells (DCs) after productive immune synapses (postsynaptic DCs) with T cells during antigen presentation has been largely neglected in favour of deciphering the nuances of T cell activation and memory generation. Here, we describe that postsynaptic DCs switch their transcriptomic signature, correlating with epigenomic changes including DNA accessibility and histone methylation. We focused on the chemokine receptor Ccr7 as a proof-of-concept gene that is increased in postsynaptic DCs. Consistent with our epigenomic observations, postsynaptic DCs migrate more efficiently toward the CCR7 ligand, the chemokine CCL19, in vitro and display enhanced homing to draining lymph nodes (dLN) in vivo.
Furthermore, these DCs increase the expression of antiviral genes such as Isg15, which confers protection against subsequent viral infections. Henceforth, we assessed the role of ISG15 in DCdeficient for this gene. Although, reduced MHCII surface expression is found after LPS maturation, no significant differences in DCs maturation were observed in response to TLR agonists. Moreover, Isg15deficient DCs secrete reduced amounts of pro-inflammatory cytokines, including IL-1β and IL-12. Once a DC is mature, it will take the path towards a dLN. However, the lack of ISG15 does not affect DCs migration capability towards CCL21 in vitro or dLNs in vivo. Once in the dLN, DCs carrying a specific antigen present it via MHC to T cell lymphocytes which are not affected in terms of T cell activation and proliferation when ISG15 is absent. Thus, ISG15 absence is apparently affecting DC cytokine secretion. However, the specific mechanism is still uncovered. It would be of great interest to decipher whether this effect is due to ISG15 conjugation to proteins or its role as a free soluble molecule.
Finally, over the years ISG15 has been on the spotlight of studies on pathogen infection or cancer development. However, recent studies suggest a role in inflammatory and other immune diseases. Isg15 is up-regulated in human psoriatic skin and mutations in this gene display dermatological alterations. Here, we observed that the absence of ISG15 leads to a reduced inflammation and swelling in a murine model of allergic contact dermatitis (ACD). Our data indicate that immune cells derived from bone marrow, and particularly DCs might be the immune cell subset accounting for this effect.
Hence, our work describes a previously unknown DC population whose transcriptomic, epigenomic profiles, and migratory capacity change in response to their cognate contact with T cells. In addition, we found that the lack of ISG15 in DCs provokes a reduced pro-inflammatory cytokine secretion and reduced inflammation in a model of ACD. This study can open new avenues to potentiate immunotherapies based on DCs or develop new therapeutics to treat certain immune dermatological condition
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