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1.
Immunity ; 51(5): 840-855.e5, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31606264

RESUMO

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes , Fator 1 de Transcrição de Linfócitos T/metabolismo , Transcrição Genética , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Fator 1 de Transcrição de Linfócitos T/genética , Viroses/genética , Viroses/imunologia , Viroses/virologia
2.
J Clin Invest ; 129(8): 3185-3200, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31264971

RESUMO

T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.


Assuntos
Linfonodos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Ducto Torácico/imunologia , Animais , Feminino , Humanos , Linfonodos/citologia , Macaca mulatta , Masculino , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Ducto Torácico/citologia
3.
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
4.
Sci Immunol ; 3(24)2018 06 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.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Memória Imunológica , Tecido Linfoide/citologia , Adulto , Animais , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/imunologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Análise de Sequência de RNA , Análise de Célula Única/métodos , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia , Adulto Jovem
5.
J Exp Med ; 215(6): 1531-1542, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29769249

RESUMO

T follicular regulatory (Tfr) cells are a population of CD4+ T cells that express regulatory T cell markers and have been shown to suppress humoral immunity. However, the precise mechanisms and location of Tfr-mediated suppression in the lymph node (LN) microenvironment are unknown. Using highly multiplexed quantitative imaging and functional assays, we examined the spatial distribution, suppressive function, and preferred interacting partners of Tfr cells in human mesenteric LNs. We find that the majority of Tfr cells express low levels of PD-1 and reside at the border between the T cell zone and B cell follicle, with very few found in the germinal centers (GCs). Although PD-1+ Tfr cells expressed higher levels of CD38, CTLA-4, and GARP than PD-1Neg Tfr cells, both potently suppressed antibody production in vitro. These findings highlight the phenotypic diversity of human Tfr cells and suggest that Tfr-mediated suppression is most efficient at the T-B border and within the follicle, not in the GC.


Assuntos
Linfonodos/imunologia , Linfócitos T Reguladores/imunologia , Formação de Anticorpos/imunologia , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Centro Germinativo/imunologia , Humanos , Lectinas Tipo C/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Receptores CXCR5/metabolismo , Transcrição Genética
6.
Trends Mol Med ; 23(12): 1072-1087, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29137933

RESUMO

CD4+ T cells play a critical role in the response to chronic viral infections during the acute phase and in the partial containment of infections once chronic infection is established. As infection persists, the virus-specific CD4+ T cell response begins to shift in phenotype. The predominant change described in both mouse and human studies of chronic viral infection is a decrease in detectable T helper type (Th)1 responses. Some Th1 loss is due to decreased proliferative potential and decreased cytokine production in the setting of chronic antigen exposure. However, recent data suggest that Th1 dysfunction is accompanied by a shift in the differentiation pathway of virus-specific CD4+ T cells, with enrichment for cells with a T follicular helper cell (Tfh) phenotype. A Tfh-like program during chronic infection has now been identified in virus-specific CD8+ T cells as well. In this review, we discuss what is known about CD4+ T cell differentiation in chronic viral infections, with a focus on the emergence of the Tfh program and the implications of this shift with respect to Tfh function and the host-pathogen interaction.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Viroses/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos
7.
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
8.
Nature ; 520(7547): 373-7, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25754329

RESUMO

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.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/radioterapia , Linfócitos T/efeitos dos fármacos , Linfócitos T/efeitos da radiação , Animais , Antígeno B7-H1/metabolismo , Feminino , Humanos , Melanoma/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos da radiação
9.
PLoS One ; 9(7): e102766, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25032989

RESUMO

OBJECTIVES: Guidelines recommend hepatitis C virus (HCV) screening for all people living with HIV (PLWH). Understanding HCV testing practices may improve compliance with guidelines and can help identify areas for future intervention. METHODS: We evaluated HCV screening and unnecessary repeat HCV testing in 8,590 PLWH initiating care at 12 U.S. HIV clinics between 2006 and 2010, with follow-up through 2011. Multivariable logistic regression examined the association between patient factors and the outcomes: HCV screening (≥1 HCV antibody tests during the study period) and unnecessary repeat HCV testing (≥1 HCV antibody tests in patients with a prior positive test result). RESULTS: Overall, 82% of patients were screened for HCV, 18% of those screened were HCV antibody-positive, and 40% of HCV antibody-positive patients had unnecessary repeat HCV testing. The likelihood of being screened for HCV increased as the number of outpatient visits rose (adjusted odds ratio 1.02, 95% confidence interval 1.01-1.03). Compared to men who have sex with men (MSM), patients with injection drug use (IDU) were less likely to be screened for HCV (0.63, 0.52-0.78); while individuals with Medicaid were more likely to be screened than those with private insurance (1.30, 1.04-1.62). Patients with heterosexual (1.78, 1.20-2.65) and IDU (1.58, 1.06-2.34) risk compared to MSM, and those with higher numbers of outpatient (1.03, 1.01-1.04) and inpatient (1.09, 1.01-1.19) visits were at greatest risk of unnecessary HCV testing. CONCLUSIONS: Additional efforts to improve compliance with HCV testing guidelines are needed. Leveraging health information technology may increase HCV screening and reduce unnecessary testing.


Assuntos
Infecções por HIV/virologia , Hepacivirus/imunologia , Hepatite C/imunologia , Hepatite C/virologia , Adolescente , Adulto , Feminino , Infecções por HIV/imunologia , Necessidades e Demandas de Serviços de Saúde , Anticorpos Anti-Hepatite C/imunologia , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Risco , Fatores de Risco , Abuso de Substâncias por Via Intravenosa/imunologia , Abuso de Substâncias por Via Intravenosa/virologia , Adulto Jovem
10.
Curr Opin Infect Dis ; 25(4): 445-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22766649

RESUMO

PURPOSE OF REVIEW: Multidrug-resistant (MDR) bacteria can cause serious infections in solid-organ transplant recipients. This review focuses on the role of MDR bacteria in posttransplant infections. RECENT FINDINGS: The incidence of MDR bacterial infections among solid-organ transplant recipients is increasing steadily. There is wide variability in the specific MDR bacteria causing infection based on the organ transplanted, geography, timing with respect to transplantation, and additional risk factors. Rarely these infections can be transmitted via the transplanted organ. Prompt recognition and early appropriate treatment of MDR bacterial infections are especially critical in this immunosuppressed population. In order to promptly initiate appropriate antimicrobial therapy for these organisms, high-risk patients should receive appropriate broad-spectrum antibiotics. SUMMARY: MDR bacterial infections vary widely and require careful antibiotic selection to reduce mortality.


Assuntos
Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana Múltipla , Transplante de Órgãos/efeitos adversos , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/enzimologia , Humanos , Fatores de Risco
11.
ScientificWorldJournal ; 10: 298-300, 2010 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-20191241

RESUMO

Sarcoidosis, a granulomatous disorder of unknown etiology, primarily affects the lungs and lymph nodes. Extrapulmonary disease without any pulmonary involvement is rare. Sarcoidosis with an elevated serum CA-125 level has only been reported five times in the literature. We describe a case of localized hepatosplenic sarcoidosis, confirmed by biopsy, with associated CA-125 elevation. In our review of the current literature, this is the first reported case of localized hepatosplenic sarcoidosis with associated serum CA-125 elevation.


Assuntos
Antígeno Ca-125/sangue , Hepatopatias/diagnóstico , Sarcoidose/diagnóstico , Esplenopatias/diagnóstico , Humanos , Hepatopatias/sangue , Hepatopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Radiografia , Sarcoidose/sangue , Sarcoidose/diagnóstico por imagem , Esplenopatias/sangue , Esplenopatias/diagnóstico por imagem
12.
Mol Ther ; 11(1): 35-47, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15585404

RESUMO

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.


Assuntos
Doenças Ósseas/prevenção & controle , Otopatias/prevenção & controle , Oftalmopatias/prevenção & controle , Terapia Genética , Cardiopatias/prevenção & controle , Fígado/enzimologia , Mucopolissacaridose I/genética , Mucopolissacaridose I/terapia , Animais , Animais Recém-Nascidos , Doenças Ósseas/complicações , Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/genética , DNA/administração & dosagem , DNA/metabolismo , Cães , Otopatias/complicações , Otopatias/genética , Otopatias/fisiopatologia , Oftalmopatias/complicações , Oftalmopatias/genética , Oftalmopatias/fisiopatologia , Cardiopatias/complicações , Cardiopatias/genética , Cardiopatias/patologia , Iduronidase/deficiência , Iduronidase/genética , Iduronidase/metabolismo , Manose/metabolismo , Camundongos , Camundongos Knockout , Mucopolissacaridose I/complicações , Mucopolissacaridose I/enzimologia , Radiografia , Retroviridae/genética , Resultado do Tratamento
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