RESUMEN
Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti-PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.
Asunto(s)
Enfermedad de Hodgkin , Inhibidores de Puntos de Control Inmunológico , Inhibidores de las Cinasas Janus , Nitrilos , Nivolumab , Pirazoles , Pirimidinas , Linfocitos T , Adulto , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sinergismo Farmacológico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/terapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Inhibidores de las Cinasas Janus/uso terapéutico , Quinasas Janus/metabolismo , Quinasas Janus/antagonistas & inhibidores , Nitrilos/uso terapéutico , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Linfocitos T/inmunología , Ratones Endogámicos C57BL , Ratones Endogámicos BALB CRESUMEN
Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.
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Fiebre de Lassa , Humanos , Fiebre de Lassa/genética , Fiebre de Lassa/diagnóstico , Fiebre de Lassa/epidemiología , Estudio de Asociación del Genoma Completo , Estudios Seroepidemiológicos , Virus Lassa/genética , Fiebre , Genética HumanaRESUMEN
INTRODUCTION: Lassa virus is a priority pathogen for vaccine research and development, however the duration of cellular immunity and protection in Lassa fever (LF) survivors remains unclear. METHODS: We investigated Lassa virus specific CD8+ T cell responses in 93 LF survivors. Peripheral blood mononuclear cells from these individuals were infected with recombinant vesicular stomatitis virus encoding Lassa virus antigens and virus specific T cell responses were measured after 18-hour incubation. Participants who had undetectable CD8+ T cell response underwent further analysis using a 10-day T cell proliferation assays to evaluate for low T cell precursor frequency. RESULTS: Forty-five of the 93 LF survivors did not have a Lassa virus specific CD8+ T cell response. Of those with responses and a known date of onset of LF (N = 11), 9 had LF within the last ten years. Most participants without a measurable CD8+ T cell response were more than 10 years removed from a clinical history of LF (N = 14/16). Fourteen of 21 patients (67%) with undetectable CD8+ T cell response had a measurable Lassa virus specific CD8+ T cell response with the 10-day assay. DISCUSSION: Despite reports of strong CD8+ T cell responses during acute Lassa virus infection, circulating Lassa virus-specific CD8+ T cells declined to undetectable levels in most Lassa fever survivors after ten years when evaluated with an 18-hour T cell stimulation. However, when Lassa virus-specific T cells were expanded prior to restimulation, a Lassa virus-specific CD8+ T cell response could be detected in many if the samples that were negative in the 18-hour stimulation assay, suggesting that prolonged cellular immunity does exist in Lassa fever survivors at low frequencies.
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Fiebre de Lassa , Células Precursoras de Linfocitos T , Humanos , Virus Lassa , Leucocitos Mononucleares , Inmunidad , Linfocitos T CD8-positivosRESUMEN
Recent studies have identified a critical role for B cell-produced cytokines in regulating both humoral and cellular immunity. Here, we show that B cells are an essential source of interleukin-27 (IL-27) during persistent lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl-13) infection. By using conditional knockout mouse models with specific IL-27p28 deletion in B cells, we observed that B cell-derived IL-27 promotes survival of virus-specific CD4 T cells and supports functions of T follicular helper (Tfh) cells. Mechanistically, B cell-derived IL-27 promotes CD4 T cell function, antibody class switch, and the ability to control persistent LCMV infection. Deletion of IL-27ra in T cells demonstrated that T cell-intrinsic IL-27R signaling is essential for viral control, optimal CD4 T cell responses, and antibody class switch during persistent LCMV infection. Collectively, our findings identify a cellular mechanism whereby B cell-derived IL-27 drives antiviral immunity and antibody responses through IL-27 signaling on T cells to promote control of LCMV Cl-13 infection.
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Linfocitos B/metabolismo , Interleucina-27/metabolismo , Coriomeningitis Linfocítica/inmunología , Inmunidad Adaptativa , Animales , Anticuerpos Antivirales , Linfocitos T CD4-Positivos/inmunología , Citocinas/metabolismo , Inmunidad Celular , Interleucina-27/genética , Interleucinas , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Mature male mice produce a particularly high concentration of major urinary proteins (MUPs) in their scent marks that provide identity and status information to conspecifics. Darcin (MUP20) is inherently attractive to females and, by inducing rapid associative learning, leads to specific attraction to the individual male's odour and location. Other polymorphic central MUPs, produced at much higher abundance, bind volatile ligands that are slowly released from a male's scent marks, forming the male's individual odour that females learn. Here, we show that infection of C57BL/6 males with LCMV WE variants (v2.2 or v54) alters MUP expression according to a male's infection status and ability to clear the virus. MUP output is substantially reduced during acute adult infection with LCMV WE v2.2 and when males are persistently infected with LCMV WE v2.2 or v54. Infection differentially alters expression of darcin and, particularly, suppresses expression of a male's central MUP signature. However, following clearance of acute v2.2 infection through a robust virus-specific CD8 cytotoxic T cell response that leads to immunity to the virus, males regain their normal mature male MUP pattern and exhibit enhanced MUP output by 30 days post-infection relative to uninfected controls. We discuss the likely impact of these changes in male MUP signals on female attraction and mate selection. As LCMV infection during pregnancy can substantially reduce embryo survival and lead to lifelong infection in surviving offspring, we speculate that females use LCMV-induced changes in MUP expression both to avoid direct infection from a male and to select mates able to develop immunity to local variants that will be inherited by their offspring.
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Coriomeningitis Linfocítica/complicaciones , Virus de la Coriomeningitis Linfocítica/patogenicidad , Proteínas/metabolismo , Animales , Femenino , Péptidos y Proteínas de Señalización Intercelular/genética , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Odorantes , Feromonas/metabolismo , Proteínas/análisis , Proteínas/genéticaRESUMEN
During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos T CD8-positivos/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Infección Persistente/inmunología , Inmunidad Adaptativa , Animales , Antivirales/uso terapéutico , Infecciones por Arenaviridae/tratamiento farmacológico , Infecciones por Arenaviridae/virología , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Linfocitos T CD4-Positivos/inmunología , Virus de la Coriomeningitis Linfocítica/efectos de los fármacos , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Ratones Endogámicos C57BL , Proteínas de la Nucleocápside/inmunología , Infección Persistente/tratamiento farmacológico , Infección Persistente/virología , Ribavirina/uso terapéutico , Carga Viral , Replicación Viral/efectos de los fármacosRESUMEN
The sphingosine-1-phosphate (S1P) is a lysophospholipid signaling molecule with important functions in many physiological and pathological conditions, including viral infection. In this issue of EMBO Molecular Medicine, Marfia et al present a risk stratification based on S1P serum level as a novel prognostic indicator for COVID-19 severity.
Asunto(s)
COVID-19 , Humanos , Lisofosfolípidos , Medición de Riesgo , SARS-CoV-2 , Esfingosina/análogos & derivadosRESUMEN
BACKGROUND: Ebola virus (EBOV) disease has killed thousands of West and Central Africans over the past several decades. Many who survive the acute disease later experience post-Ebola syndrome, a constellation of symptoms whose causative pathogenesis is unclear. METHODS: We investigated EBOV-specific CD8+ and CD4+ T-cell responses in 37 Sierra Leonean EBOV disease survivors with (n = 19) or without (n = 18) sequelae of arthralgia and ocular symptoms. Peripheral blood mononuclear cells were infected with recombinant vesicular stomatitis virus encoding EBOV antigens. We also studied the presence of EBOV-specific immunoglobulin G, antinuclear antibodies, anti-cyclic citrullinated peptide antibodies, rheumatoid factor, complement levels, and cytokine levels in these 2 groups. RESULTS: Survivors with sequelae had a significantly higher EBOV-specific CD8+ and CD4+ T-cell response. No differences in EBOV-specific immunoglobulin G, antinuclear antibody, or anti-cyclic citrullinated peptide antibody levels were found. Survivors with sequelae showed significantly higher rheumatoid factor levels. CONCLUSION: EBOV-specific CD8+ and CD4+ T-cell responses were significantly higher in Ebola survivors with post-Ebola syndrome. These findings suggest that pathogenesis may occur as an immune-mediated disease via virus-specific T-cell immune response or that persistent antigen exposure leads to increased and sustained T-cell responses.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/inmunología , Adulto , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Femenino , Técnica del Anticuerpo Fluorescente , Fiebre Hemorrágica Ebola/patología , Humanos , Inmunidad Celular , Masculino , Sierra Leona/epidemiología , SobrevivientesRESUMEN
Early and robust T cell responses have been associated with survival from Lassa fever (LF), but the Lassa virus-specific memory responses have not been well characterized. Regions within the virus surface glycoprotein (GPC) and nucleoprotein (NP) are the main targets of the Lassa virus-specific T cell responses, but, to date, only a few T cell epitopes within these proteins have been identified. We identified GPC and NP regions containing T cell epitopes and HLA haplotypes from LF survivors and used predictive HLA-binding algorithms to identify putative epitopes, which were then experimentally tested using autologous survivor samples. We identified 12 CD8-positive (CD8+) T cell epitopes, including epitopes common to both Nigerian and Sierra Leonean survivors. These data should be useful for the identification of dominant Lassa virus-specific T cell responses in Lassa fever survivors and vaccinated individuals as well as for designing vaccines that elicit cell-mediated immunity.IMPORTANCE The high morbidity and mortality associated with clinical cases of Lassa fever, together with the lack of licensed vaccines and limited and partially effective interventions, make Lassa virus (LASV) an important health concern in its regions of endemicity in West Africa. Previous infection with LASV protects from disease after subsequent exposure, providing a framework for designing vaccines to elicit similar protective immunity. Multiple major lineages of LASV circulate in West Africa, and therefore, ideal vaccine candidates should elicit immunity to all lineages. We therefore sought to identify common T cell epitopes between Lassa fever survivors from Sierra Leone and Nigeria, where distinct lineages circulate. We identified three such epitopes derived from highly conserved regions within LASV proteins. In this process, we also identified nine other T cell epitopes. These data should help in the design of an effective pan-LASV vaccine.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/química , Fiebre de Lassa/inmunología , Virus Lassa/inmunología , Nucleoproteínas/inmunología , Proteínas del Envoltorio Viral/inmunología , Adolescente , Secuencia de Aminoácidos , Animales , Anticuerpos Antivirales/biosíntesis , Antígenos Virales/química , Antígenos Virales/genética , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/virología , Niño , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Femenino , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/inmunología , Haplotipos , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Sueros Inmunes/análisis , Memoria Inmunológica , Fiebre de Lassa/genética , Fiebre de Lassa/patología , Virus Lassa/patogenicidad , Masculino , Nigeria , Nucleoproteínas/genética , Sierra Leona , Sobrevivientes , Proteínas del Envoltorio Viral/genética , Adulto JovenRESUMEN
Lassa virus infects hundreds of thousands of people each year across rural West Africa, resulting in a high number of cases of Lassa fever (LF), a febrile disease associated with high morbidity and significant mortality. The lack of approved treatments or interventions underscores the need for an effective vaccine. At least four viral lineages circulate in defined regions throughout West Africa with substantial interlineage nucleotide and amino acid diversity. An effective vaccine should be designed to elicit Lassa virus specific humoral and cell mediated immunity across all lineages. Most current vaccine candidates use only lineage IV antigens encoded by Lassa viruses circulating around Sierra Leone, Liberia, and Guinea but not Nigeria where lineages I-III are found. As previous infection is known to protect against disease from subsequent exposure, we sought to determine whether LF survivors from Nigeria and Sierra Leone harbor memory T cells that respond to lineage IV antigens. Our results indicate a high degree of cross-reactivity of CD8+ T cells from Nigerian LF survivors to lineage IV antigens. In addition, we identified regions within the Lassa virus glycoprotein complex and nucleoprotein that contributed to these responses while T cell epitopes were not widely conserved across our study group. These data are important for current efforts to design effective and efficient vaccine candidates that can elicit protective immunity across all Lassa virus lineages.
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Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos de Linfocito T/inmunología , Virus Lassa/inmunología , África Occidental , Reacciones Cruzadas , Femenino , Humanos , Masculino , Especificidad de la EspecieRESUMEN
Inhibitory receptors (IRs) function as critical regulators of immune responses by tempering T cell activity. In humans, several persisting viruses as well as cancers exploit IR signaling by upregulating IR ligands, resulting in suppression of T cell function (i.e., exhaustion). This allows escape from immune surveillance and continuation of disease. Here, we report the design, implementation, and results of a phenotypic high-throughput screen for molecules that modulate CD8+ T cell activity. We identify 19 compounds from the ReFRAME drug-repurposing collection that restore cytokine production and enhance the proliferation of exhausted T cells. Analysis of our top hit, ingenol mebutate, a protein kinase C (PKC) inducing diterpene ester, reveals a role for this molecule in overriding the suppressive signaling cascade mediated by IR signaling on T cells. Collectively, these results demonstrate a disease-relevant methodology for identifying modulators of T cell function and reveal new targets for immunotherapy.
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Linfocitos T CD8-positivos/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Citocinas/metabolismo , Inmunoterapia/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa C/metabolismo , Transducción de Señal/efectos de los fármacos , Células VeroRESUMEN
Lymphocytic choriomeningitis virus (LCMV) WE variant 2.2 (v2.2) generated a high level of the major mouse urinary protein: MUP. Mice infected with LCMV WE v54, which differed from v2.2 by a single amino acid in the viral glycoprotein, failed to generate MUP above baseline levels found in uninfected controls. Variant 54 bound at 2.5 logs higher affinity to the LCMV receptor α-dystroglycan (α-DG) than v2.2 and entered α-DG-expressing but not α-DG-null cells. Variant 2.2 infected both α-DG-null or -expressing cells. Variant 54 infected more dendritic cells, generated a negligible CD8 T cell response, and caused a persistent infection, while v2.2 generated cytotoxic T lymphocytes (CTLs) and cleared virus within 10 days. By 20 days postinfection and through the 80-day observation period, significantly higher amounts of MUP were found in v2.2-infected mice. Production of MUP was dependent on virus-specific CTL as deletion of such cells aborted MUP production. Furthermore, MUP production was not elevated in v2.2 persistently infected mice unless virus was cleared following transfer of virus-specific CTL.
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Linfocitos T CD8-positivos/inmunología , Regulación de la Expresión Génica/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Proteínas/inmunología , Animales , Distroglicanos/inmunología , Coriomeningitis Linfocítica/patología , RatonesRESUMEN
INTRODUCTION: Live attenuated zoster vaccine (Zostavax) was used to test the hypothesis that constitutive level of interleukin 10 (IL-10), which may be high in elderly subjects, impairs vaccine efficacy. If constitutive IL-10 impairs vaccine efficacy, the effectiveness of viral vaccines might be improved by transient inhibition of IL-10 before vaccination. METHODS: Zostavax was given to 26 patients (age, 60-80 years). IL-10 and immunity to varicella zoster virus (VZV) were measured at baseline and after vaccination. Fluorescent antibody to membrane antigen (FAMA) assays and glycoprotein enzyme-linked immunosorbent assays (gpELISAs) were used to assess humoral immunity; anti-varicella virus T-cell responses were studied in a subset of subjects. In a prospective animal model, T-cell responses to chimeric vaccines against lymphocytic choriomeningitis virus (LCMV) were assessed in mice that express or lack IL-10. RESULTS: FAMA assays revealed significant boosting (by 4-fold) of humoral immunity, which occurred only in subjects (10 of 26) with a low constitutive IL-10 level (ie, <20 pg/mL); moreover, the Zostavax-induced FAMA and gpELISA responses were inversely related to the constitutive IL-10 level. Significant VZV-specific T-cell responses followed vaccination only in subjects with a low constitutive IL-10 level. Vaccine-induced LCMV-specific T-cell responses in mice lacking IL-10 were greater than in wild-type animals. CONCLUSIONS: A high constitutive IL-10 level adversely affects vaccine efficacy.
Asunto(s)
Vacuna contra el Herpes Zóster/inmunología , Herpesvirus Humano 3/inmunología , Interleucina-10/sangre , Anciano , Anciano de 80 o más Años , Animales , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Inmunidad Humoral/inmunología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana EdadRESUMEN
Viruses have long been implicated in the pathogenesis of autoimmunity, yet their contribution remains circumstantial partly due to the lack of well-documented information on infections prior to autoimmune disease onset. Here, we used the lymphocytic choriomeningitis virus (LCMV) as a model to mechanistically dissect the impact of viral infection on lupus-like autoimmunity. Virus persistence strongly enhanced disease in mice with otherwise weak genetic predisposition but not in highly predisposed or non-autoimmune mice, indicating a synergistic interplay between genetic susceptibility and virus infection. Moreover, endosomal Toll-like receptors (TLRs) and plasmacytoid dendritic cells (pDCs) were both strictly required for disease acceleration, even though LCMV also induces strong TLR-independent type I interferon (IFN-I) production via RNA helicases and MAVS in conventional DCs. These results suggest that LCMV enhances systemic autoimmunity primarily by providing stimulatory nucleic acids for endosomal TLR engagement, whereas overstimulation of the MAVS-dependent cytosolic pathway in the absence of endosomal TLR signaling is insufficient for disease induction.
Asunto(s)
Autoinmunidad , Endosomas/inmunología , Lupus Eritematoso Sistémico/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica , Receptores Toll-Like/metabolismo , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Autoinmunidad/genética , Células Cultivadas , Células Dendríticas/inmunología , Células Dendríticas/virología , Modelos Animales de Enfermedad , Endosomas/virología , Femenino , Predisposición Genética a la Enfermedad , Interferón Tipo I/metabolismo , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/virología , Coriomeningitis Linfocítica/genética , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Transducción de SeñalRESUMEN
Understanding of T cell exhaustion and successful therapy to restore T cell function was first described using Clone (Cl) 13 variant selected from the lymphocytic choriomeningitis virus (LCMV) Armstrong (ARM) 53b parental strain. T cell exhaustion plays a pivotal role in both persistent infections and cancers of mice and humans. C57BL/6, BALB, SWR/J, A/J, 129, C3H, and all but one collaborative cross (CC) mouse strain following Cl 13 infection have immunosuppressed T cell responses, high PD-1, and viral titers leading to persistent infection and normal life spans. In contrast, the profile of FVB/N, NZB, PL/J, SL/J, and CC NZO mice challenged with Cl 13 is a robust T cell response, high titers of virus, PD-1, and Lag3 markers on T cells. These mice all die 7 to 9 d after Cl 13 infection. Death is due to enhanced pulmonary endothelial vascular permeability, pulmonary edema, collapse of alveolar air spaces, and respiratory failure. Pathogenesis involves abundant levels of Cl 13 receptor alpha-dystroglycan on endothelial cells, with high viral replication in such cells leading to immunopathologic injury. Death is aborted by blockade of interferon-1 (IFN-1) signaling or deletion of CD8 T cells.
Asunto(s)
Linfocitos T CD8-positivos , Interferón Tipo I , Coriomeningitis Linfocítica , Virus de la Coriomeningitis Linfocítica/fisiología , Replicación Viral/genética , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Humanos , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/metabolismo , Coriomeningitis Linfocítica/patología , Ratones , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
The recent Ebola epidemic exemplified the importance of understanding and controlling emerging infections. Despite the importance of T cells in clearing virus during acute infection, little is known about Ebola-specific CD8+ T cell responses. We investigated immune responses of individuals infected with Ebola virus (EBOV) during the 2013-2016 West Africa epidemic in Sierra Leone, where the majority of the >28,000 EBOV disease (EVD) cases occurred. We examined T cell memory responses to seven of the eight Ebola proteins (GP, sGP, NP, VP24, VP30, VP35, and VP40) and associated HLA expression in survivors. Of the 30 subjects included in our analysis, CD8+ T cells from 26 survivors responded to at least one EBOV antigen. A minority, 10 of 26 responders (38%), made CD8+ T cell responses to the viral GP or sGP. In contrast, 25 of the 26 responders (96%) made response to viral NP, 77% to VP24 (20 of 26), 69% to VP40 (18 of 26), 42% (11 of 26) to VP35, with no response to VP30. Individuals making CD8+ T cells to EBOV VP24, VP35, and VP40 also made CD8+ T cells to NP, but rarely to GP. We identified 34 CD8+ T cell epitopes for Ebola. Our data indicate the immunodominance of the EBOV NP-specific T cell response and suggest that its inclusion in a vaccine along with the EBOV GP would best mimic survivor responses and help boost cell-mediated immunity during vaccination.
Asunto(s)
Anticuerpos Antivirales/inmunología , Linfocitos T CD8-positivos/inmunología , Ebolavirus/inmunología , Epidemias , Antígenos HLA/inmunología , Fiebre Hemorrágica Ebola/inmunología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Antígenos Virales/inmunología , Epítopos de Linfocito T/inmunología , Femenino , Antígenos HLA/sangre , Fiebre Hemorrágica Ebola/sangre , Fiebre Hemorrágica Ebola/epidemiología , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Masculino , Nucleoproteínas/inmunología , Sierra Leona , Sobrevivientes , Vacunación/métodos , Proteínas Virales/inmunología , Adulto JovenRESUMEN
Blockade of IFN-α but not IFN-ß signaling using either an antibody or a selective S1PR1 agonist, CYM-5442, prevented type 1 diabetes (T1D) in the mouse Rip-LCMV T1D model. First, treatment with antibody or CYM-5442 limited the migration of autoimmune "antiself" T cells to the external boundaries around the islets and prevented their entry into the islets so they could not be positioned to engage, kill, and thus remove insulin-producing ß cells. Second, CYM-5442 induced an exhaustion signature in antiself T cells by up-regulating the negative immune regulator receptor genes Pdcd1, Lag3, Ctla4, Tigit, and Btla, thereby limiting their killing ability. By such means, insulin production was preserved and glucose regulation maintained, and a mechanism for S1PR1 immunomodulation described.
Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Indanos/administración & dosificación , Interferón-alfa/metabolismo , Oxadiazoles/administración & dosificación , Estado Prediabético/tratamiento farmacológico , Receptores de Lisoesfingolípidos/agonistas , Linfocitos T/efectos de los fármacos , Animales , Diabetes Mellitus Tipo 1/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Indanos/farmacología , Insulina/metabolismo , Células Secretoras de Insulina/inmunología , Islotes Pancreáticos/inmunología , Ratones , Oxadiazoles/farmacología , Estado Prediabético/inmunología , Receptores Inmunológicos/metabolismo , Transducción de Señal/efectos de los fármacos , Receptores de Esfingosina-1-Fosfato , Linfocitos T/inmunologíaAsunto(s)
Selección de Profesión , Ciencia , Virología , Historia del Siglo XX , Historia del Siglo XXI , Humanos , VirosisRESUMEN
Type I interferon (IFN-I) elicits a complex cascade of events in response to microbial infection. Here, we review recent developments illuminating the large number of IFN-I species and describing their unique biologic functions.
Asunto(s)
Infecciones Bacterianas/inmunología , Interferón Tipo I/metabolismo , Virosis/inmunología , Animales , Infecciones Bacterianas/microbiología , Humanos , Interferón Tipo I/química , Interferón Tipo I/inmunología , Receptor de Interferón alfa y beta/metabolismo , Virosis/virologíaRESUMEN
Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and down-modulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions.