RESUMEN
Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.
Asunto(s)
Inmunogenicidad Vacunal/inmunología , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Células T Auxiliares Foliculares/metabolismo , Animales , Anticuerpos/inmunología , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Antígenos/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Vacunas contra Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/patogenicidad , Humanos , Inmunidad Humoral/inmunología , Inmunogenicidad Vacunal/fisiología , Proteína Antagonista del Receptor de Interleucina 1/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/inmunología , Receptores de Interleucina-1/metabolismo , Células T Auxiliares Foliculares/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Vacunación/métodosRESUMEN
Humanized mice represent a suitable preclinical test system for example therapeutic interventions in various disease settings, including infections. Here, we intended to establish such system for cutaneous leishmaniasis by infecting T, B and NK cell-deficient mice adoptively transferred with human peripheral blood mononuclear cells (PBMC). L major infection led to the establishment of parasite lesions harbouring viable parasites and human T cells, but parasite elimination was not seen due to a species-specific activity of T cell-derived human IFNγ. In addition, up to 50% of infected mice succumbed to severe graft-versus-host disease. In summary, even though long-term disease outcome assessments are impossible, this model of humanized mice can be used for studying lesion development and generation of oligoclonal anti-parasite human T cell responses in vivo.
Asunto(s)
Traslado Adoptivo , Leishmaniasis Cutánea/terapia , Leucocitos Mononucleares/trasplante , Subgrupos de Linfocitos T/trasplante , Traslado Adoptivo/efectos adversos , Animales , Progresión de la Enfermedad , Enfermedad Injerto contra Huésped/etiología , Xenoinjertos , Humanos , Interferón gamma/farmacología , Leishmaniasis Cutánea/parasitología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Ratones , Modelos Animales , Especificidad de la Especie , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Exhaustion of cytotoxic effector natural killer (NK) and CD8+ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/OTg mice permissive for persistent HCV infection, that NK and CD8+ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8+ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8+ T cell functions to prevent persistent HCV infection.
Asunto(s)
Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Células Asesinas Naturales/inmunología , Subfamília C de Receptores Similares a Lectina de Células NK/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Citocinas/inmunología , Modelos Animales de Enfermedad , Hepatitis C Crónica/virología , Hepatocitos/virología , Antígenos de Histocompatibilidad Clase I/inmunología , Interferón gamma/inmunología , Activación de Linfocitos/fisiología , Proteínas de la Membrana/inmunología , Ratones , Distribución AleatoriaRESUMEN
T cells are key players in autoimmune diseases by supporting the production of autoantibodies. However, their contribution to the effector phase of antibody-mediated autoimmune dermatoses, i.e., tissue injury and inflammation of the skin, has not been investigated. In this paper, we demonstrate that T cells amplify the development of autoantibody-induced tissue injury in a prototypical, organ-specific autoimmune disease, namely epidermolysis bullosa acquisita (EBA) - characterized and caused by autoantibodies targeting type VII collagen. Specifically, we show that immune complex (IC)-induced inflammation depends on the presence of T cells - a process facilitated by T cell receptor (TCR)γδ and NKT cells. Because tissue damage in IC-induced inflammation is neutrophil-dependent, we further analyze the interplay between T cells and neutrophils in an experimental model of EBA. We demonstrate that T cells not only enhance neutrophil recruitment into the site of inflammation but also interact with neutrophils in lymphatic organs. Collectively, this study shows that T cells amplify the effector phase of antibody-induced tissue inflammation.