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1.
Artigo em Inglês | MEDLINE | ID: mdl-31445098

RESUMO

BACKGROUND: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numerical and/or functional T helper cell alterations. The causes, interrelationships and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia and/or autoantibody production remain unclear. OBJECTIVE: To determine how circulating CD4+ T-cells are altered in CVID subjects with autoimmune cytopenias (CVID+AIC) and the causes of these derrangements. METHODS: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large, genetically diverse CVID subject cohort (n=69) using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection and a suite of in vitro functional assays measuring naive T cell differentiation, B cell/T cell co-cultures and Treg suppression. RESULTS: Whereas CD4+ T helper cell profiles from healthy donors and CVID subjects without autoimmune cytopenias were virtually indistinguishable, CVID+AIC T cells exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and ICOSL. The resulting enlarged CVID+AIC circulating Tfh (cTfh) cell population provided efficient help to receptive HD B cells but not unresponsive CVID B cells. Despite this, CVID+AIC cTfh exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with Treg suppression assays and were associated with autoantibody production. CONCLUSIONS: Endotoxemia is associated with early commitment to the follicular T cell lineage in IgA-deficient CVID subjects, particularly those with AICs.

2.
Nature ; 571(7764): 211-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207603

RESUMO

Exhausted CD8+ T (Tex) cells in chronic infections and cancer have limited effector function, high co-expression of inhibitory receptors and extensive transcriptional changes compared with effector (Teff) or memory (Tmem) CD8+ T cells. Tex cells are important clinical targets of checkpoint blockade and other immunotherapies. Epigenetically, Tex cells are a distinct immune subset, with a unique chromatin landscape compared with Teff and Tmem cells. However, the mechanisms that govern the transcriptional and epigenetic development of Tex cells remain unknown. Here we identify the HMG-box transcription factor TOX as a central regulator of Tex cells in mice. TOX is largely dispensable for the formation of Teff and Tmem cells, but it is critical for exhaustion: in the absence of TOX, Tex cells do not form. TOX is induced by calcineurin and NFAT2, and operates in a feed-forward loop in which it becomes calcineurin-independent and sustained in Tex cells. Robust expression of TOX therefore results in commitment to Tex cells by translating persistent stimulation into a distinct Tex cell transcriptional and epigenetic developmental program.

3.
Cell Rep ; 27(7): 2063-2074.e5, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091446

RESUMO

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer.

4.
Nat Med ; 25(3): 454-461, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804515

RESUMO

Immunologic responses to anti-PD-1 therapy in melanoma patients occur rapidly with pharmacodynamic T cell responses detectable in blood by 3 weeks. It is unclear, however, whether these early blood-based observations translate to the tumor microenvironment. We conducted a study of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV melanoma. We hypothesized that immune reinvigoration in the tumor would be detectable at 3 weeks and that this response would correlate with disease-free survival. We identified a rapid and potent anti-tumor response, with 8 of 27 patients experiencing a complete or major pathological response after a single dose of anti-PD-1, all of whom remain disease free. These rapid pathologic and clinical responses were associated with accumulation of exhausted CD8 T cells in the tumor at 3 weeks, with reinvigoration in the blood observed as early as 1 week. Transcriptional analysis demonstrated a pretreatment immune signature (neoadjuvant response signature) that was associated with clinical benefit. In contrast, patients with disease recurrence displayed mechanisms of resistance including immune suppression, mutational escape, and/or tumor evolution. Neoadjuvant anti-PD-1 treatment is effective in high-risk resectable stage III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to predict clinical outcome and to dissect underlying mechanisms in checkpoint blockade.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Procedimentos Cirúrgicos Dermatológicos , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos , Quimioterapia Adjuvante , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia , Transcriptoma , Evasão Tumoral
5.
Z Gastroenterol ; 57(1): 74-86, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30641606

RESUMO

The success of immune modulation by checkpoint blockade approaches is currently transforming oncology, with high and long-lasting tumor responses in patients with advanced disease across many cancer entities. Rooted in the reinvigoration of adaptive antitumor immune responses through disinhibition of negative feedback pathways, these approaches are particularly effective in patients with significant preexisting T cell responses in tumors with high neoantigen load. While promising data is starting to emerge from clinical trials in liver cancer patients, the underlying immunobiology remains poorly understood. In this review, we discuss the immunological mechanisms underlying the success of current checkpoint blockade therapies and the implications for hepatology including management of immune-related hepatitis. Checkpoint blockade therapy provides novel therapeutic options for difficult-to-treat liver cancers but also novel clinical challenges for hepatologists facing immune-related adverse events.


Assuntos
Imunoterapia , Neoplasias Hepáticas/terapia , Antígeno B7-H1 , Antígeno CTLA-4 , Gastroenterologia , Hepatite Autoimune , Humanos , Receptor de Morte Celular Programada 1
6.
Gut ; 68(5): 905-915, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30622109

RESUMO

OBJECTIVE: A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. DESIGN: By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. RESULTS: HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. CONCLUSIONS: Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Produtos do Gene pol/metabolismo , Vírus da Hepatite B/imunologia , Hepatite B Crônica/metabolismo , Proteínas do Core Viral/metabolismo , Carga Viral , Adulto , Idoso , Estudos de Coortes , Feminino , Hepatite B Crônica/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
7.
PLoS One ; 13(12): e0208225, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30507970

RESUMO

BACKGROUND & AIMS: Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients. METHODS: In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS. RESULTS: In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases. CONCLUSIONS: A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.

8.
Sci Immunol ; 3(24)2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29858286

RESUMO

Current paradigms of CD8+ T cell-mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8+ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs Moreover, high frequencies of HIV-specific CD8+ TRMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8+ T cell responses resident within LTs.

9.
Immunity ; 48(5): 1029-1045.e5, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29768164

RESUMO

Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a transcriptomic- and epigenetic-guided mass cytometry approach to define core exhaustion-specific genes and disease-induced changes in Tex cells in HIV and human cancer. Single-cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns. An exhaustion severity metric was developed and integrated with high-dimensional phenotypes to define Tex cell clusters that were present in healthy subjects, common across chronic infection and cancer or enriched in either disease, linked to disease severity, and changed with HIV therapy. Combinatorial patterns of immunotherapy targets on different Tex cell clusters were also defined. This approach and associated datasets present a resource for investigating human Tex cell biology, with implications for immune monitoring and immunomodulation in chronic infections, autoimmunity, and cancer.

10.
Hepatology ; 68(6): 2089-2105, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29729204

RESUMO

The liver bears unique immune properties that support both immune tolerance and immunity, but the mechanisms responsible for clearance versus persistence of virus-infected hepatocytes remain unclear. Here, we dissect the factors determining the outcome of antiviral immunity using recombinant adenoviruses that reflect the hepatropism and hepatrophism of hepatitis viruses. We generated replication-deficient adenoviruses with equimolar expression of ovalbumin, luciferase, and green fluorescent protein driven by a strong ubiquitous cytomegalovirus (CMV) promoter (Ad-CMV-GOL) or by 100-fold weaker, yet hepatocyte-specific, transthyretin (TTR) promoter (Ad-TTR-GOL). Using in vivo bioluminescence to quantitatively and dynamically image luciferase activity, we demonstrated that Ad-TTR-GOL infection always persists, whereas Ad-CMV-GOL infection is always cleared, independent of the number of infected hepatocytes. Failure to clear Ad-TTR-GOL infection involved mechanisms acting during initiation as well as execution of antigen-specific immunity. First, hepatocyte-restricted antigen expression led to delayed and curtailed T-cell expansion-10,000-fold after Ad-CMV-GOL versus 150-fold after Ad-TTR-GOL-infection. Second, CD8 T-cells primed toward antigens selectively expressed by hepatocytes showed high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression levels similar to that seen in chronic hepatitis B. Third, Ad-TTR-GOL but not Ad-CMV-GOL-infected hepatocytes escaped being killed by effector T-cells while still inducing high PD-1/Tim-3/LAG-3/CTLA-4/CD160 expression, indicating different thresholds of T-cell receptor signaling relevant for triggering effector functions compared with exhaustion. Conclusion: Our study identifies deficits in the generation of CD8 T-cell immunity toward hepatocyte-expressed antigens and escape of infected hepatocytes expressing low viral antigen levels from effector T-cell killing as independent factors promoting viral persistence. This highlights the importance of addressing both the restauration of CD8 T-cell dysfunction and overcoming local hurdles of effector T-cell function to eliminate virus-infected hepatocytes.

12.
J Immunol Methods ; 453: 3-10, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28322863

RESUMO

The elimination of infected or tumor cells by direct lysis is a key T and NK cell effector function. T and NK cells can kill target cells by coordinated secretion of cytotoxic granules containing one or both pore-forming proteins, perforin and granulysin and combinations of granzyme (Gzm) family effector proteases (in humans: Gzm A, B, K, M and H). Understanding the pattern of expression of cytotoxic molecules and the relationship to different states of T and NK cells may have direct relevance for immune responses in autoimmunity, infectious disease and cancer. Approaches capable of simultaneously evaluating expression of multiple cytotoxic molecules with detailed information on T and NK differentiation state, however, remain limited. Here, we established a high dimensional mass cytometry approach to comprehensively interrogate single cell proteomic expression of cytotoxic programs and lymphocyte differentiation. This assay identified a coordinated expression pattern of cytotoxic molecules linked to CD8 T cell differentiation stages. Coordinated high expression of perforin, granulysin, Gzm A, Gzm B and Gzm M was associated with markers of late effector memory differentiation and expression of chemokine receptor CX3CR1. However, classical gating and dimensionality reduction approaches also identified other discordant patterns of cytotoxic molecule expression in CD8 T cells, including reduced perforin, but high Gzm A, Gzm K and Gzm M expression. When applied to non-CD8 T cells, this assay identified different patterns of cytotoxic molecule co-expression by CD56hi versus CD56dim defined NK cell developmental stages; in CD4 T cells, low expression of cytotoxic molecules was found mainly in TH1 phenotype cells, but not in Tregs or T follicular helper cells (TFH). Thus, this comprehensive, single cell, proteomic assessment of cytotoxic protein co-expression patterns demonstrates specialized cytotoxic programs in T cells and NK cells linked to their differentiation stages. Such comprehensive cytotoxic profiling may identify distinct patterns of cytotoxic potential relevant for specific infections, autoimmunity or tumor settings.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Células Matadoras Naturais/fisiologia , Espectrometria de Massas/métodos , Proteínas Citotóxicas Formadoras de Poros/isolamento & purificação , Células Th1/imunologia , Antígeno CD56/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo , Diferenciação Celular , Células Cultivadas , Citotoxicidade Imunológica , Voluntários Saudáveis , Humanos , Memória Imunológica , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Proteômica , Análise de Célula Única
13.
Immunity ; 47(4): 723-738.e5, 2017 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-29031786

RESUMO

Noroviruses can establish chronic infections with active viral shedding in healthy humans but whether persistence is associated with adaptive immune dysfunction is unknown. We used genetically engineered strains of mouse norovirus (MNV) to investigate CD8+ T cell differentiation during chronic infection. We found that chronic infection drove MNV-specific tissue-resident memory (Trm) CD8+ T cells to a differentiation state resembling inflationary effector responses against latent cytomegalovirus with only limited evidence of exhaustion. These MNV-specific Trm cells remained highly functional yet appeared ignorant of ongoing viral replication. Pre-existing MNV-specific Trm cells provided partial protection against chronic infection but largely ceased to detect virus within 72 hours of challenge, demonstrating rapid sequestration of viral replication away from T cells. Our studies revealed a strategy of immune evasion by MNV via the induction of a CD8+ T cell program normally reserved for latent pathogens and persistence in an immune-privileged enteric niche.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Caliciviridae/imunologia , Diferenciação Celular/imunologia , Gastroenterite/imunologia , Norovirus/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Infecções por Caliciviridae/genética , Infecções por Caliciviridae/virologia , Diferenciação Celular/genética , Linhagem Celular , Microambiente Celular/genética , Microambiente Celular/imunologia , Gastroenterite/genética , Gastroenterite/virologia , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Células HEK293 , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Camundongos Endogâmicos C57BL , Norovirus/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos
14.
Nat Protoc ; 12(9): 1980-1998, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28858287

RESUMO

Retroviral (RV) expression of genes of interest (GOIs) is an invaluable tool and has formed the foundation of cellular engineering for adoptive cell therapy in cancer and other diseases. However, monitoring of transduced T cells long term (weeks to months) in vivo remains challenging because of the low frequency and often poor durability of transduced T cells over time when transferred without enrichment. Traditional methods often require additional overnight in vitro culture after transduction. Moreover, in vitro-generated effector CD8+ T cells enriched by sorting often have reduced viability, making it difficult to monitor the fate of transferred cells in vivo. Here, we describe an optimized mouse CD8+ T-cell RV transduction protocol that uses simple and rapid Percoll density centrifugation to enrich RV-susceptible activated CD8+ T cells. Percoll density centrifugation is simple, can be done on the day of transduction, requires minimal time, has low reagent costs and improves cell recovery (up to 60%), as well as the frequency of RV-transduced cells (∼sixfold over several weeks in vivo as compared with traditional methods). We have used this protocol to assess the long-term stability of CD8+ T cells after RV transduction by comparing the durability of T cells transduced with retroviruses expressing each of six commonly used RV reporter genes. Thus, we provide an optimized enrichment and transduction approach that allows long-term in vivo assessment of RV-transduced T cells. The overall procedure from T-cell isolation to RV transduction takes 2 d, and enrichment of activated T cells can be done in 1 h.


Assuntos
Linfócitos T CD8-Positivos/virologia , Vetores Genéticos/genética , Retroviridae/genética , Transdução Genética/métodos , Animais , Camundongos
15.
Sci Immunol ; 2(8)2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28620653

RESUMO

T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTfh, have similarity to lymphoid Tfh, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner and whether they form long-lasting memory. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38. This subset expressed more Bcl-6, c-Maf, and IL-21 than other blood CD4 subsets. Influenza vaccination induced a strong response in the ICOS+CD38+ cTfh at day 7, and this population included hemagglutinin-specific cells by tetramer staining and antigen-stimulated Activation Induced Marker (AIM) expression. Moreover, TCRB sequencing identified a clonal response in ICOS+CD38+ cTfh that correlated strongly with the increased circulating ICOS+CD38+ cTfh frequency and the circulating plasmablast response. In subjects who received successive annual vaccinations, a recurrent oligoclonal response was identified in the ICOS+CD38+ cTfh subset at 7 days after every vaccination. These oligoclonal responses in ICOS+CD38+ cTfh after vaccination persisted in the ICOS-CD38- cTfh repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more-stable ICOS-CD38- cTfh subset. These data highlight the antigen-specificity, lineage relationships and memory properties of human cTfh responses to vaccination, providing new avenues for tracking and monitoring cTfh responses during infection and vaccination in humans.

16.
World J Gastroenterol ; 23(16): 3003-3010, 2017 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-28522919

RESUMO

Protein-losing enteropathy (PLE) is characterized by loss of serum proteins into the gastrointestinal tract. It may lead to hypoproteinemia and clinically present as protein deficiency edema, ascites, pleural or pericardial effusion and/or malnutrition. In most cases the site of protein loss is the small intestine. Here we present an unusual case of severe PLE in a 55-year old female with a one-year history of recurrent diarrhea, crampy abdominal pain, and peripheral edema. Endoscopy and MRI showed a diffuse inflammatory thickening of the sigmoid colon and the rectum. Surgical resection of the involved colon was performed and the symptoms were significantly resolved. The final histologic evaluation confirmed a diagnosis of a pseudomembranous colitis with cap polyposis-like features. Such a cause of PLE has never been described before.


Assuntos
Colo , Pólipos do Colo/complicações , Enterocolite Pseudomembranosa/complicações , Enteropatias Perdedoras de Proteínas/etiologia , Biópsia , Colectomia , Colo/imunologia , Colo/patologia , Colo/cirurgia , Pólipos do Colo/diagnóstico , Pólipos do Colo/cirurgia , Colonoscopia , Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/cirurgia , Feminino , Humanos , Imuno-Histoquímica , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Enteropatias Perdedoras de Proteínas/diagnóstico , Índice de Gravidade de Doença , Resultado do Tratamento
17.
Nature ; 545(7652): 60-65, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28397821

RESUMO

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/tratamento farmacológico , Melanoma/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Carga Tumoral/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Antígeno Ki-67/imunologia , Antígeno Ki-67/metabolismo , Masculino , Melanoma/irrigação sanguínea , Melanoma/patologia , Estadiamento de Neoplasias , Fenótipo , Resultado do Tratamento
18.
Clin Liver Dis ; 20(4): 629-644, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27742004

RESUMO

Hepatitis B virus (HBV) infection is a major global health challenge. HBV can cause significant morbidity and mortality by establishing acute and chronic hepatitis. Approximately 250 million people worldwide are chronically infected, and more than 2 billion people have been exposed to HBV. Since the discovery of HBV, the advances in our understanding of HBV virology and immunology have translated into effective vaccines and therapies for HBV infection. Although current therapies successfully suppress viral replication but rarely succeed in viral eradication, recent discoveries in HBV virology and immunology provide exciting rationales for novel treatment strategies aiming at HBV cure.


Assuntos
Anticorpos Anti-Hepatite B/imunologia , Antígenos da Hepatite B/imunologia , Vacinas contra Hepatite B/farmacologia , Vírus da Hepatite B/fisiologia , Hepatite B , Vacinação/métodos , Replicação Viral/imunologia , Hepatite B/imunologia , Hepatite B/prevenção & controle , Hepatite B/virologia , Humanos
19.
Science ; 354(6316): 1160-1165, 2016 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-27789795

RESUMO

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.


Assuntos
Antígeno B7-H1/genética , Linfócitos T CD8-Positivos/imunologia , Reprogramação Celular/genética , Epigênese Genética , Memória Imunológica/genética , Animais , Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/transplante , Linhagem da Célula/genética , Reprogramação Celular/imunologia , Feminino , Redes Reguladoras de Genes , Imunoterapia , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Genética
20.
Immunity ; 45(2): 358-73, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27496729

RESUMO

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.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Animais , Anticorpos Neutralizantes/farmacologia , Antígeno B7-H1/imunologia , Células Cultivadas , Reprogramação Celular , Senescência Celular , Metabolismo Energético , Glucose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptor de Morte Celular Programada 1/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
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