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1.
Nat Immunol ; 15(4): 373-83, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24584090

RESUMEN

The transcription factor BATF is required for the differentiation of interleukin 17 (IL-17)-producing helper T cells (TH17 cells) and follicular helper T cells (TFH cells). Here we identified a fundamental role for BATF in regulating the differentiation of effector of CD8(+) T cells. BATF-deficient CD8(+) T cells showed profound defects in effector population expansion and underwent proliferative and metabolic catastrophe early after encountering antigen. BATF, together with the transcription factors IRF4 and Jun proteins, bound to and promoted early expression of genes encoding lineage-specific transcription-factors (T-bet and Blimp-1) and cytokine receptors while paradoxically repressing genes encoding effector molecules (IFN-γ and granzyme B). Thus, BATF amplifies T cell antigen receptor (TCR)-dependent expression of transcription factors and augments the propagation of inflammatory signals but restrains the expression of genes encoding effector molecules. This checkpoint prevents irreversible commitment to an effector fate until a critical threshold of downstream transcriptional activity has been achieved.


Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Linfocitos T CD8-positivos/inmunología , Proteínas de Dominio T Box/metabolismo , Células Th17/inmunología , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/inmunología , Diferenciación Celular/genética , Procesos de Crecimiento Celular/genética , Células Cultivadas , Regulación hacia Abajo , Granzimas/genética , Granzimas/metabolismo , Factores Reguladores del Interferón/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Activación de Linfocitos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-jun/metabolismo , Proteínas de Dominio T Box/genética , Factores de Transcripción/genética , Activación Transcripcional/genética
2.
Immunity ; 45(2): 358-73, 2016 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-27496729

RESUMEN

Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Animales , Anticuerpos Neutralizantes/farmacología , Antígeno B7-H1/inmunología , Células Cultivadas , Reprogramación Celular , Senescencia Celular , Metabolismo Energético , Glucosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Receptor de Muerte Celular Programada 1/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo
3.
Immunity ; 40(2): 289-302, 2014 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-24530057

RESUMEN

T cell exhaustion is common during chronic infections. Although CD4(+) T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and transcriptional program. We defined the phenotypic, functional, and molecular profiles of exhausted CD4(+) T cells. Global transcriptional analysis demonstrated a molecular profile distinct from effector and memory CD4(+) T cells and also from exhausted CD8(+) T cells, though some common features of CD4(+) and CD8(+) T cell exhaustion were revealed. We have demonstrated unappreciated roles for transcription factors (TFs) including Helios, type I interferon (IFN-I) signaling, and a diverse set of coinhibitory and costimulatory molecules during CD4(+) T cell exhaustion. Moreover, the signature of CD4(+) T cell exhaustion was found to be distinct from that of other CD4(+) T cell lineage subsets and was associated with TF heterogeneity. This study provides a framework for therapeutic interventions targeting exhausted CD4(+) T cells.


Asunto(s)
Infecciones Bacterianas/inmunología , Linfocitos T CD4-Positivos/inmunología , Enfermedades Transmisibles/inmunología , Virosis/inmunología , Carga Bacteriana , Linfocitos T CD4-Positivos/citología , Enfermedad Crónica , Enfermedades Transmisibles/fisiopatología , Humanos , Carga Viral
4.
Nature ; 520(7547): 373-7, 2015 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-25754329

RESUMEN

Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Puntos de Control del Ciclo Celular/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Melanoma/radioterapia , Linfocitos T/efectos de los fármacos , Linfocitos T/efectos de la radiación , Animales , Antígeno B7-H1/metabolismo , Femenino , Humanos , Melanoma/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/efectos de los fármacos , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de la radiación
5.
J Immunol ; 197(4): 1017-22, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27430722

RESUMEN

The role of Ab and B cells in preventing infection is established. In contrast, the role of B cell responses in containing chronic infections remains poorly understood. IgG2a (IgG1 in humans) can prevent acute infections, and T-bet promotes IgG2a isotype switching. However, whether IgG2a and B cell-expressed T-bet influence the host-pathogen balance during persisting infections is unclear. We demonstrate that B cell-specific loss of T-bet prevents control of persisting viral infection. T-bet in B cells controlled IgG2a production, as well as mucosal localization, proliferation, glycosylation, and a broad transcriptional program. T-bet controlled a broad antiviral program in addition to IgG2a because T-bet in B cells was important, even in the presence of virus-specific IgG2a. Our data support a model in which T-bet is a universal controller of antiviral immunity across multiple immune lineages.


Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Coriomeningitis Linfocítica/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Separación Celular , Enfermedad Crónica , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunoglobulina G/inmunología , Virus de la Coriomeningitis Linfocítica , Ratones , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos
6.
J Immunol ; 188(7): 2957-65, 2012 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-22442493

RESUMEN

Costimulatory and inhibitory receptors are critical regulators of adaptive immune cell function. These pathways regulate the initiation and termination of effective immune responses to infections while limiting autoimmunity and/or immunopathology. This review focuses on recent advances in our understanding of inhibitory receptor pathways and their roles in different diseases and/or infections, emphasizing potential clinical applications and important unanswered mechanistic questions. Although significant progress has been made in defining the influence of inhibitory receptors at the cellular level, relatively little is known about the underlying molecular pathways. We discuss our current understanding of the molecular mechanisms for key inhibitory receptor pathways, highlight major gaps in knowledge, and explore current and future clinical applications.


Asunto(s)
Inmunidad Adaptativa , Infecciones/inmunología , Subgrupos Linfocitarios/inmunología , Receptores Inmunológicos/inmunología , Secuencias de Aminoácidos , Anticuerpos Monoclonales/uso terapéutico , Antígeno CTLA-4/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Regulación de la Expresión Génica/inmunología , Genes de Inmunoglobulinas , Humanos , Lectinas Tipo C/inmunología , Ligandos , Activación de Linfocitos/inmunología , Terapia Molecular Dirigida , Familia de Multigenes , Fosfoproteínas Fosfatasas/fisiología , Fosforilación , Receptor de Muerte Celular Programada 1/inmunología , Procesamiento Proteico-Postraduccional
7.
Commun Med (Lond) ; 3(1): 2, 2023 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-36596885

RESUMEN

BACKGROUND: Remdesivir (RDV) is an intravenous antiviral with activity against SARS-CoV-2 for treatment of hospitalized COVID-19 patients with moderate-to-severe disease. Biomarkers associated with clinical outcomes have been identified for COVID-19, but few evaluated in context of antiviral treatment. Here, we assessed baseline (day 1, prior to first RDV dose) biomarkers and the impact of RDV treatment on longitudinal biomarker readouts. METHODS: Recently, RDV was evaluated in high-risk, non-hospitalized patients with confirmed SARS-CoV-2 infection and was highly effective at preventing disease progression. The randomized, double-blind, placebo-controlled Phase 3 study included 562 participants who received at least 1 dose of study drug, of which 312 consented for longitudinal biomarker assessments at baseline, day 3, and day 14. We assessed sixteen baseline biomarkers and the impact of RDV treatment on longitudinal biomarker readouts. RESULTS: Six well-known, inflammation-associated biomarkers are elevated at baseline in participants meeting the primary endpoint of hospitalization or death by day 28. Moreover, in comparison to placebo, biomarkers in RDV-treated participants show accelerated improvement, including reduction of soluble angiopoietin-2, D-dimer, and neutrophil-to-lymphocyte ratio, as well as an increase in lymphocyte counts. CONCLUSIONS: Overall, the findings in this study suggest that RDV treatment may accelerate the improvement of multiple biomarkers of COVID-19 severity, which are associated with better clinical outcomes during infection. These findings have implications for better understanding the activity of antiviral treatments in COVID-19.


Certain cells and proteins in the blood can act as markers of COVID-19 severity. However, little is known about the impact of antiviral treatments on these markers. Here, we measured protein and cell markers in patient samples before treatment and those taken during the course of COVID-19 in high-risk non-hospitalized patients treated with or without the antiviral remdesivir (RDV). Several markers were improved with RDV treatment, including those associated with normal responses from the immune system and factors involved in blood clotting. These findings further our understanding of the activity of antivirals in COVID-19 and inform future studies to understand how patients with an increased risk of COVID-19 disease progression respond to these treatments.

8.
JHEP Rep ; 5(4): 100664, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36908748

RESUMEN

Background & Aims: Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from individuals with chronic hepatitis B and evaluated sampling heterogeneity, effects of disease stage, and nucleos(t)ide (NUC) treatment, and correlations between liver and peripheral viral biomarkers. Methods: Hepatocytes positive for HBV core and HBsAg were quantified using a novel four-plex immunofluorescence assay and image analysis. Biopsies were analysed from HBeAg-positive (n = 39) and HBeAg-negative (n = 75) participants before and after NUC treatment. To evaluate sampling effects, duplicate biopsies collected at the same time point were compared. Serum or plasma samples were evaluated for levels of HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA. Results: Diffusely distributed individual HBV core+ cells and foci of HBsAg+ cells were the most common staining patterns. Hepatocytes positive for both HBV core and HBsAg were rare. Paired biopsies revealed large local variation in HBV staining within participants, which was confirmed in a large liver resection. NUC treatment was associated with a >100-fold lower median frequency of HBV core+ cells in HBeAg-positive and HBeAg-negative participants, whereas reductions in HBsAg+ cells were not statistically significant. The frequency of HBV core+ hepatocytes was lower in HBeAg-negative participants than in HBeAg-positive participants at all time points evaluated. Total HBV+ hepatocyte burden correlated with HBcrAg, HBV DNA, and HBV RNA only in baseline HBeAg-positive samples. Conclusions: Reductions in HBV core+ hepatocytes were associated with HBeAg-negative status and NUC treatment. Variation in HBV positivity within individual livers was extensive. Correlations between the liver and the periphery were found only between biomarkers likely indicative of cccDNA (HBV core+ and HBcrAg, HBV DNA, and RNA). Impact and Implications: HBV infects liver hepatocyte cells, and its genome can exist in two forms that express different sets of viral proteins: a circular genome called cccDNA that can express all viral proteins, including the HBV core and HBsAg proteins, or a linear fragment that inserts into the host genome typically to express HBsAg, but not HBV core. We used new techniques to determine the percentage of hepatocytes expressing the HBV core and HBsAg proteins in a large set of liver biopsies. We find that abundance and patterns of expression differ across patient groups and even within a single liver and that NUC treatment greatly reduces the number of core-expressing hepatocytes.

9.
Cell Rep ; 39(7): 110815, 2022 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-35584677

RESUMEN

Although generating high neutralizing antibody levels is a key component of protective immunity after acute viral infection or vaccination, little is known about why some individuals generate high versus low neutralizing antibody titers. Here, we leverage the high-dimensional single-cell profiling capacity of mass cytometry to characterize the longitudinal cellular immune response to Zika virus (ZIKV) infection in viremic blood donors in Puerto Rico. During acute ZIKV infection, we identify widely coordinated responses across innate and adaptive immune cell lineages. High frequencies of multiple activated cell types during acute infection are associated with high titers of ZIKV neutralizing antibodies 6 months post-infection, while stable immune features suggesting a cytotoxic-skewed immune set point are associated with low titers. Our study offers insight into the coordination of immune responses and identifies candidate cellular biomarkers that may offer predictive value in vaccine efficacy trials aimed at inducing high levels of antiviral neutralizing antibodies.


Asunto(s)
Infección por el Virus Zika , Virus Zika , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Humanos , Vacunación
10.
Cell Rep ; 31(13): 107827, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32610128

RESUMEN

The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Subtipo H3N2 del Virus de la Influenza A/fisiología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de Señal , Administración Intranasal , Animales , Muerte Celular/inmunología , Diferenciación Celular/inmunología , Proliferación Celular , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/patología , Especificidad de la Especie
11.
Sci Transl Med ; 10(463)2018 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-30333241

RESUMEN

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, we assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. We found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria-exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.


Asunto(s)
Reactividad Cruzada/inmunología , Malaria/inmunología , Linfocitos T/inmunología , Antígenos de Protozoos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Proliferación Celular , Citocinas/metabolismo , Femenino , Feto/inmunología , Humanos , Memoria Inmunológica , Lactante , Mediadores de Inflamación/metabolismo , Péptidos/inmunología , Embarazo
12.
J Clin Invest ; 127(1): 103-105, 2017 01 03.
Artículo en Inglés | MEDLINE | ID: mdl-27941242

RESUMEN

While antiretroviral therapy (ART) has improved the quality of life and increased the life span of many HIV-infected individuals, this therapeutic strategy has several limitations, including a lack of efficacy in fully restoring immune function and a requirement for life-long treatment. Two studies in this issue of the JCI use a humanized mouse model and demonstrate that type I interferon (IFN) is induced early during HIV infection and that type I IFN-associated gene signatures persist, even during ART. Importantly, blockade of type I IFN improved immune function, reduced the HIV reservoir, and caused a delay in viral rebound after ART interruption. Together, these two studies support further evaluation of IFN blockade as a supplement to ART.


Asunto(s)
Antirretrovirales/farmacología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Interferón Tipo I/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Ratones
13.
Trends Mol Med ; 22(10): 877-888, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27614925

RESUMEN

Pregnancy-associated malaria, including placental malaria, causes significant morbidity and mortality worldwide. Recently, it has been suggested that in utero exposure of the fetus to malaria antigens may negatively impact the developing immune system and result in tolerance to malaria. Here, we review our current knowledge of fetal immunity to malaria, focusing on the dynamic interactions between maternal malaria infection, placental development, and the fetal immune system. A better understanding of the long-term impact of in utero malaria exposure on the development of natural immunity to malaria, immune responses to other childhood pathogens, and vaccine immunogenicity is urgently needed. This may guide the implementation of novel chemoprevention strategies during pregnancy and facilitate the push toward malaria vaccines.


Asunto(s)
Feto/inmunología , Inmunidad , Malaria/inmunología , Complicaciones Parasitarias del Embarazo/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Linfocitos T/inmunología , Femenino , Feto/citología , Feto/patología , Humanos , Tolerancia Inmunológica , Inmunidad Celular , Inmunidad Innata , Transmisión Vertical de Enfermedad Infecciosa , Malaria/complicaciones , Malaria/epidemiología , Malaria/patología , Embarazo , Complicaciones Parasitarias del Embarazo/epidemiología , Complicaciones Parasitarias del Embarazo/patología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/patología
14.
Science ; 354(6316): 1160-1165, 2016 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-27789795

RESUMEN

Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.


Asunto(s)
Antígeno B7-H1/genética , Linfocitos T CD8-positivos/inmunología , Reprogramación Celular/genética , Epigénesis Genética , Memoria Inmunológica/genética , Animales , Antígeno B7-H1/antagonistas & inhibidores , Linfocitos T CD8-positivos/trasplante , Linaje de la Célula/genética , Reprogramación Celular/inmunología , Femenino , Redes Reguladoras de Genes , Inmunoterapia , Interleucina-7/metabolismo , Ratones , Ratones Endogámicos C57BL , Transcripción Genética
15.
J Exp Med ; 212(7): 1125-37, 2015 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-26034050

RESUMEN

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Coriomeningitis Linfocítica/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Traslado Adoptivo , Animales , Bromodesoxiuridina , Diferenciación Celular/genética , Proliferación Celular/fisiología , Citometría de Flujo , Ratones , Receptor de Muerte Celular Programada 1/deficiencia
16.
Cancer Immunol Res ; 3(4): 399-411, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25678581

RESUMEN

Disabling the function of immune checkpoint molecules can unlock T-cell immunity against cancer, yet despite remarkable clinical success with monoclonal antibodies (mAb) that block PD-1 or CTLA-4, resistance remains common and essentially unexplained. To date, pancreatic carcinoma is fully refractory to these antibodies. Here, using a genetically engineered mouse model of pancreatic ductal adenocarcinoma in which spontaneous immunity is minimal, we found that PD-L1 is prominent in the tumor microenvironment, a phenotype confirmed in patients; however, tumor PD-L1 was found to be independent of IFNγ in this model. Tumor T cells expressed PD-1 as prominently as T cells from chronically infected mice, but treatment with αPD-1 mAbs, with or without αCTLA-4 mAbs, failed in well-established tumors, recapitulating clinical results. Agonist αCD40 mAbs with chemotherapy induced T-cell immunity and reversed the complete resistance of pancreatic tumors to αPD-1 and αCTLA-4. The combination of αCD40/chemotherapy plus αPD-1 and/or αCTLA-4 induced regression of subcutaneous tumors, improved overall survival, and conferred curative protection from multiple tumor rechallenges, consistent with immune memory not otherwise achievable. Combinatorial treatment nearly doubled survival of mice with spontaneous pancreatic cancers, although no cures were observed. Our findings suggest that in pancreatic carcinoma, a nonimmunogenic tumor, baseline refractoriness to checkpoint inhibitors can be rescued by the priming of a T-cell response with αCD40/chemotherapy.


Asunto(s)
Antígeno B7-H1/inmunología , Antígeno CTLA-4/inmunología , Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Subgrupos de Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígenos CD40/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Carcinoma Ductal Pancreático/inmunología , Línea Celular Tumoral , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Ingeniería Genética/métodos , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Inmunidad Celular , Interferón gamma/inmunología , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/inmunología , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Gemcitabina , Neoplasias Pancreáticas
17.
Science ; 338(6111): 1220-5, 2012 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-23197535

RESUMEN

Chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling this regenerative capacity, however, are unknown. We found that two distinct states of virus-specific CD8(+) T cells exist in chronically infected mice and humans. Differential expression of the T-box transcription factors T-bet and Eomesodermin (Eomes) facilitated the cooperative maintenance of the pool of antiviral CD8(+) T cells during chronic viral infection. T-bet(hi) cells displayed low intrinsic turnover but proliferated in response to persisting antigen, giving rise to Eomes(hi) terminal progeny. Genetic elimination of either subset resulted in failure to control chronic infection, which suggests that an imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Hepatitis B Crónica/inmunología , Proteínas de Dominio T Box/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Humanos , Hígado/virología , Activación de Linfocitos , Ratones , Ratones Noqueados , Células Madre/inmunología , Proteínas de Dominio T Box/genética
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