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1.
Brain ; 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33723591

RESUMO

The concerted actions of the CNS and the immune system are essential to coordinate the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model in which the hedgehog signaling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signaling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signaling regulates the pathogenic profile of CD4 T cells by limiting their production of inflammatory cytokines GM-CSF and IFN-γ and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signaling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS, but also propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation.

2.
Immunity ; 52(5): 825-841.e8, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32396847

RESUMO

CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Transcrição Genética/imunologia , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Epigênese Genética/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/imunologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Neoplasias/genética , Neoplasias/terapia , Proteínas com Domínio T/genética , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcrição Genética/genética
3.
Proc Natl Acad Sci U S A ; 116(24): 11916-11925, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31138702

RESUMO

The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNA Morrbid is specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, the Morrbid RNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor, Bcl2l11, and by modulating the strength of the PI3K-AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , RNA Longo não Codificante/imunologia , Animais , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/imunologia , Interferon Tipo I/imunologia , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia
4.
Viruses ; 11(2)2019 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-30691215

RESUMO

Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.


Assuntos
Modelos Animais de Doenças , Imunoterapia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Animais , Ensaios Clínicos como Assunto , Humanos , Imunoterapia Adotiva , Coriomeningite Linfocítica/terapia , Vírus da Coriomeningite Linfocítica/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Linfócitos T/imunologia , Linfócitos T/patologia
5.
Annu Rev Immunol ; 37: 457-495, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30676822

RESUMO

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.


Assuntos
Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Imunoterapia/métodos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia , Viroses/imunologia , Animais , Senescência Celular , Doença Crônica , Anergia Clonal , Epigênese Genética , Humanos , Neoplasias/terapia , Viroses/terapia
6.
Sci Rep ; 7(1): 2495, 2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28566716

RESUMO

Direct acting antivirals against hepatitis C virus (HCV) have markedly improved cure rates in the past few years. However, they are expensive, with only few targeting host cell factors, and affecting virus assembly and release. Huh7.5 cells infected with a JFH-1 clone of HCV were treated with two different glycogen synthase kinase (GSK3)-ß inhibitors; AR-A014418 and lithium chloride. Intra- and extracellular HCV virions and specific infectivity was determined using real-time RT-PCR and TCID50, and changes in lipid production were identified by enzyme-linked immunoassay and mass spectrometry analyses. Similarly, effect on two HCV replicon cells were identified by the luciferase activity. Although there was limited effect on virus replication in Huh7.5 cells and replicons, Huh7.5 cells treated with GSK3ß inhibitors produced significantly less viral particles in comparison to untreated cells. In addition, the treated cells synthesized significantly lower amounts of ApoB and trapped the ApoE lipoproteins in the cells. In conclusion, our study suggests that GSK3ß plays a pivotal role in HCV virion assembly and release mediated in part through inhibition of apolipoprotein synthesis.


Assuntos
Glicogênio Sintase Quinase 3 beta/genética , Hepatite C/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Apolipoproteínas B/biossíntese , Apolipoproteínas B/genética , Apolipoproteínas E/biossíntese , Apolipoproteínas E/genética , Linhagem Celular , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Hepacivirus/efeitos dos fármacos , Hepacivirus/patogenicidade , Hepatite C/genética , Hepatite C/virologia , Humanos , Cloreto de Lítio/farmacologia , Tiazóis/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia , Vírion/efeitos dos fármacos , Vírion/genética
7.
PLoS Pathog ; 13(2): e1006191, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28146579

RESUMO

The dynamics of the memory CD8 T cell receptor (TCR) repertoire upon virus re-exposure and factors governing the selection of TCR clonotypes conferring protective immunity in real life settings are poorly understood. Here, we examined the dynamics and functionality of the virus-specific memory CD8 TCR repertoire before, during and after hepatitis C virus (HCV) reinfection in patients who spontaneously resolved two consecutive infections (SR/SR) and patients who resolved a primary but failed to clear a subsequent infection (SR/CI). The TCR repertoire was narrower prior to reinfection in the SR/SR group as compared to the SR/CI group and became more focused upon reinfection. CD8 T cell clonotypes expanding upon re-exposure and associated with protection from viral persistence were recruited from the memory T cell pool. Individual CD8 T cell lines generated from the SR/SR group exhibited higher functional avidity and polyfunctionality as compared to cell lines from the SR/CI group. Our results suggest that protection from viral persistence upon HCV reinfection is associated with focusing of the HCV-specific CD8 memory T cell repertoire from which established cell lines showed high functional avidity. These findings are applicable to vaccination strategies aiming at shaping the protective human T cell repertoire.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepatite C/imunologia , Memória Imunológica/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Citometria de Fluxo , Hepacivirus/imunologia , Humanos
8.
Sci Rep ; 6: 29447, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27385120

RESUMO

The innate and adaptive immune systems fail to control HCV infection in the majority of infected individuals. HCV is an ssRNA virus, which suggests a role for Toll-like receptors (TLRs) 7 and 8 in initiating the anti-viral response. Here we demonstrate that HCV genomic RNA harbours specific sequences that initiate an anti-HCV immune response through TLR7 and TLR8 in various antigen presenting cells. Conversely, HCV particles are detected by macrophages, but not by monocytes and DCs, through a TLR7/8 dependent mechanism; this leads to chloroquine sensitive production of pro-inflammatory cytokines including IL-1ß, while the antiviral type I Interferon response is not triggered in these cells. Antibodies to DC-SIGN, a c-type lectin selectively expressed by macrophages but not pDCs or mDCs, block the production of cytokines. Novel anti-HCV vaccination strategies should target the induction of TLR7/8 stimulation in APCs in order to establish potent immune responses against HCV.


Assuntos
Células Apresentadoras de Antígenos/virologia , Hepacivirus/genética , Macrófagos/virologia , RNA Viral/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/metabolismo , Células Apresentadoras de Antígenos/imunologia , Linhagem Celular , Cloroquina/farmacologia , Células HEK293 , Hepacivirus/imunologia , Hepatite C/imunologia , Humanos , Interleucina-1beta/metabolismo , Macrófagos/metabolismo
9.
Front Immunol ; 5: 274, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24982656

RESUMO

The majority of individuals who become acutely infected with hepatitis C virus (HCV) develop chronic infection and suffer from progressive liver damage while approximately 25% are able to eliminate the virus spontaneously. Despite the recent introduction of new direct-acting antivirals, there is still no vaccine for HCV. As a result, new infections and reinfections will remain a problem in developing countries and among high risk populations like injection drug users who have limited access to treatment and who continue to be exposed to the virus. The outcome of acute HCV is determined by the interplay between the host genetics, the virus, and the virus-specific immune response. Studies in humans and chimpanzees have demonstrated the essential role of HCV-specific CD4 and CD8 T cell responses in protection against viral persistence. Recent data suggest that antibody responses play a more important role than what was previously thought. Individuals who spontaneously resolve acute HCV infection develop long-lived memory T cells and are less likely to become persistently infected upon reexposure. New studies examining high risk cohorts are identifying correlates of protection during real life exposures and reinfections. In this review, we discuss correlates of protective immunity during acute HCV and upon reexposure. We draw parallels between HCV and the current knowledge about protective memory in other models of chronic viral infections. Finally, we discuss some of the yet unresolved questions about key correlates of protection and their relevance for vaccine development against HCV.

10.
Gastroenterology ; 147(4): 870-881.e8, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25038432

RESUMO

BACKGROUND & AIMS: Development of a vaccine against hepatitis C virus (HCV) has been hindered by our limited understanding of immune correlates of protection during real-life exposure to the virus. We studied the immune response during HCV reinfection. METHODS: We analyzed blood samples from participants in the Montreal Acute Hepatitis C Injection Drug User Cohort Study who were reinfected with HCV from 2009 to 2012. Five patients spontaneously resolved their second infection and 4 developed chronic infections. We monitored the phenotypic and functional dynamics of HCV-specific memory T cell responses in all subjects during natural re-exposure and re-infection. RESULTS: Populations of CD4(+) and CD8(+) T cells with HCV-specific polyfunctional memory were expanded in all 5 individuals who resolved 2 successive HCV infections. We detected CD127(hi) HCV-specific memory CD8(+) T cells before reinfection regardless of a subject's ability to clear subsequent infections. Protection against viral persistence was associated with the expansion of a CD127(neg), PD1(lo) effector memory T cells at the peak of the response. We also observed broadening of T-cell response, indicating generation of de novo T-cell responses. The 4 individuals who failed to clear their subsequent infection had limited expansion of HCV-specific CD4(+) and CD8(+) memory T cells and expressed variable levels of the exhaustion marker PD1 on HCV-specific CD8(+) T cells. Dominant epitope regions of HCV strains isolated from patients with persistent reinfection had sequence variations that were not recognized by the pre-existing memory T cells. CONCLUSIONS: Protection from persistent HCV reinfection depends on the magnitude, breadth, and quality of the HCV-specific memory T-cell response. Sequence homology among viruses and ability of T cells to recognize multiple strains of HCV are critical determinants of protective memory.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Memória Imunológica , Antígenos Virais/sangue , Biomarcadores/sangue , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Proliferação de Células , Epitopos de Linfócito T/sangue , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/diagnóstico , Hepatite C/prevenção & controle , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-7/sangue , Ativação Linfocitária , Fenótipo , Receptor de Morte Celular Programada 1/sangue , Quebeque , RNA Viral/sangue , Prevenção Secundária , Fatores de Tempo
11.
J Virol ; 84(19): 10429-35, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20668076

RESUMO

Early alpha interferon (IFN-alpha) therapy against hepatitis C virus (HCV) rescues polyfunctional, virus-specific memory CD8(+) T cells, but whether immune restoration is possible during late therapy remains controversial. We compared immune restoration of HCV-specific memory T cells in patients who cleared HCV infection spontaneously and following early or late IFN therapy. Multifunctional CD4(+) and CD8(+) memory T cells were detected in spontaneous resolvers and in individuals treated early following an acute infection. In contrast, limited responses were detected in patients treated during chronic infection, and the phenotype of HCV-specific cells was influenced by autologous viral sequences. Our data suggest that irreversible damage to the HCV-specific memory T-cell response is associated with chronic HCV infection.


Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/imunologia , Hepatite C Crônica/terapia , Hepatite C/imunologia , Hepatite C/terapia , Interferon Tipo I/uso terapêutico , Doença Aguda , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Degranulação Celular/imunologia , Estudos de Coortes , Hepacivirus/imunologia , Hepatite C/virologia , Hepatite C Crônica/virologia , Humanos , Memória Imunológica , Interferon gama/biossíntese , Interleucina-2/biossíntese , Dados de Sequência Molecular , RNA Viral/sangue , Proteínas Recombinantes , Fatores de Tempo
12.
J Virol ; 82(20): 10017-31, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18667516

RESUMO

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-alpha) antiviral therapy achieves the highest rate of success when IFN-alpha is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-gamma- and IL-2-producing and CD107a(+)) virus-specific CD8(+) T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8(+) T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-alpha rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C , Interferon-alfa , Subpopulações de Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/citologia , Epitopos , Feminino , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Humanos , Memória Imunológica/imunologia , Interferon-alfa/imunologia , Interferon-alfa/uso terapêutico , Subunidade alfa de Receptor de Interleucina-7/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Subpopulações de Linfócitos T/citologia
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