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1.
Immunity ; 56(9): 2086-2104.e8, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37572655

RESUMO

The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.


Assuntos
Glioblastoma , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Antígeno CTLA-4 , Células Th1 , Microglia , Linfócitos T CD8-Positivos , Fagocitose , Células Dendríticas , Linfócitos T CD4-Positivos
2.
Immunity ; 54(7): 1561-1577.e7, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34102100

RESUMO

A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36-/- T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.


Assuntos
Antígenos CD36/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Peroxidação de Lipídeos/fisiologia , Lipoproteínas LDL/metabolismo , Neoplasias/metabolismo , Receptores Depuradores/metabolismo , Animais , Transporte Biológico/fisiologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Leucócitos Mononucleares/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microambiente Tumoral/fisiologia
3.
Eur J Immunol ; 50(1): 97-109, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31777067

RESUMO

The innate immune response generated against influenza infection is critical for the inhibition of viral dissemination. The trachea contains different types of innate immune cells that protect the respiratory tract from pathogen invasion. Among them, γδ T cells have the ability to rapidly generate large amounts of pro-inflammatory cytokines to preserve mucosal barrier homeostasis during infection. However, little is known about their role during the early phase of influenza infection in the airways. In this study, we found that, early after infection, γδ T cells are recruited and activated in the trachea and outnumber αß T cells during the course of the influenza infection that follows. We also showed that the majority of the recruited γδ T cells express the Vγ4 TCR chain and infiltrate in a process that involves the chemokine receptor CXCR3. In addition, we demonstrated that γδ T cells promote the recruitment of protective neutrophils and NK cells to the tracheal mucosa. Altogether, our results highlight the importance of the immune responses mediated by Î³Î´ T cells.


Assuntos
Imunidade Inata/imunologia , Interleucina-17/imunologia , Infecções por Orthomyxoviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Traqueia/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Traqueia/virologia
4.
J Immunol ; 189(3): 1491-9, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22745371

RESUMO

FcRγ is an ITAM-containing adaptor required for CD16 signaling and function in NK cells. We have previously shown that NK cells from HIV patients receiving combination antiretroviral therapy (cART) have decreased FcRγ expression, but the factors causing this are unknown. We conducted a cross-sectional study of cART-naive viremic patients (ART(-)), virologically suppressed patients receiving cART (ART(+)), and HIV-uninfected controls. CD8(+) T cells were activated, as assessed by CD38(+)HLA-DR(+) expression, in ART(-) patients (p < 0.0001), which was significantly reduced in ART(+) patients (p = 0.0005). In contrast, CD38(+)HLA-DR(+) NK cells were elevated in ART(-) patients (p = 0.0001) but did not decrease in ART(+) patients (p = 0.88). NK cells from both ART(-) and ART(+) patients showed high levels of spontaneous degranulation in ex vivo whole blood assays as well as decreased CD16 expression (p = 0.0001 and p = 0.0025, respectively), FcRγ mRNA (p < 0.0001 for both groups), FcRγ protein expression (p = 0.0016 and p < 0.0001, respectively), and CD16-dependent Syk phosphorylation (p = 0.0001 and p = 0.003, respectively). HIV-infected subjects showed alterations in NK activation, degranulation, CD16 expression and signaling, and elevated plasma markers of inflammation and macrophage activation, that is, neopterin and sCD14, which remained elevated in ART(+) patients. Alterations in NK cell measures did not correlate with viral load or CD4 counts. These data show that in HIV patients who achieve viral suppression following cART, NK cell activation persists. This suggests that NK cells respond to factors different from those driving T cell activation, but which are associated with inflammation in HIV patients.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Imunidade Inata , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Ativação Linfocitária/imunologia , Adulto , Idoso , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Doença Crônica , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Quimioterapia Combinada , Infecções por HIV/patologia , HIV-1/efeitos dos fármacos , Humanos , Imunidade Inata/efeitos dos fármacos , Células Matadoras Naturais/virologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/biossíntese , Receptores de IgG/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia
5.
Science ; 381(6664): 1316-1323, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37733872

RESUMO

Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.


Assuntos
Antígenos de Neoplasias , Complexo II de Transporte de Elétrons , Complexo I de Transporte de Elétrons , Mitocôndrias , Neoplasias , Humanos , Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/genética , Complexo II de Transporte de Elétrons/metabolismo , Elétrons , Técnicas de Inativação de Genes , Histonas/metabolismo , Proteínas de Choque Térmico HSP40/genética , Melanoma/imunologia , Melanoma/patologia , Metilação , Mitocôndrias/enzimologia , Neoplasias/imunologia , Neoplasias/patologia , Linhagem Celular Tumoral
6.
Artigo em Inglês | MEDLINE | ID: mdl-34001529

RESUMO

Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8+ T cells provide protection by actively scanning for their cognate antigen and migrating into inflamed tissues. Trafficking patterns of CD8+ T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8+ T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8+ T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8+ T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Diferenciação Celular , Memória Imunológica , Células T de Memória , Animais , Humanos
7.
Drug Deliv Transl Res ; 11(4): 1689-1702, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33797035

RESUMO

In the last few decades, nanotechnology has emerged as an important tool aimed at enhancing the immune response against modern antigens. Nanocarriers designed specifically for this purpose have been shown to provide protection, stability, and controlled release properties to proteins, peptides, and polynucleotide-based antigens. Polysaccharides are particularly interesting biomaterials for the construction of these nanocarriers given their wide distribution among pathogens, which facilitates their recognition by antigen-presenting cells (APCs). In this work, we focused on an immunostimulant beta-glucan derivative, carboxymethyl-ß-glucan, to prepare a novel nanocarrier in combination with chitosan. The resulting carboxymethyl-ß-glucan/chitosan nanoparticles exhibited adequate physicochemical properties and an important protein association efficiency, with ovalbumin as a model compound. Moreover, thermostability was achieved through the optimization of a lyophilized form of the antigen-loaded nanoparticles, which remained stable for up to 1 month at 40 ºC. Biodistribution studies in mice showed an efficient drainage of the nanoparticles to the nearest lymph node following subcutaneous injection, and a significant co-localization with dendritic cells. Additionally, subcutaneous immunization of mice with a single dose of the ovalbumin-loaded nanoparticles led to induced T cell proliferation and antibody responses, comparable to those achieved with alum-adsorbed ovalbumin. These results illustrate the potential of these novel nanocarriers in vaccination.


Assuntos
Quitosana , Nanopartículas , beta-Glucanas , Animais , Antígenos/farmacologia , Quitosana/química , Portadores de Fármacos/química , Camundongos , Nanopartículas/química , Distribuição Tecidual , beta-Glucanas/farmacologia
8.
J Exp Med ; 217(8)2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32525985

RESUMO

CD8+ tissue-resident memory T cells (TRM cells) are poised at the portals of infection and provide long-term protective immunity. Despite their critical roles, the precise mechanics governing TRM cell reactivation in situ are unknown. Using a TCR-transgenic Nur77-GFP reporter to distinguish "antigen-specific" from "bystander" reactivation, we demonstrate that lung CD8+ TRM cells are reactivated more quickly, yet less efficiently, than their counterparts in the draining LNs (TLN cells). Global profiling of reactivated memory T cells revealed tissue-defined and temporally regulated recall response programs. Unlike the reactivation of CD8+ TLN cells, which is strictly dependent on CD11c+XCR1+ APCs, numerous antigen-presenting partners, both hematopoietic and non-hematopoietic, were sufficient to reactivate lung CD8+ TRM cells, but the quality of TRM cell functional responses depended on the identity of the APCs. Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8+ memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8+ T cells.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Pulmão/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Animais , Antígenos CD11/genética , Antígenos CD11/imunologia , Camundongos , Camundongos Knockout , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/imunologia
9.
Front Immunol ; 10: 2621, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824481

RESUMO

Neutrophils are amongst the first cells to respond to inflammation and infection. Although they play a key role in limiting the dissemination of pathogens, the study of their dynamic behavior in immune organs remains elusive. In this work, we characterized in vivo the dynamic behavior of neutrophils in the mouse popliteal lymph node (PLN) after influenza vaccination with UV-inactivated virus. To achieve this, we used an image-based systems biology approach to detect the motility patterns of neutrophils and to associate them to distinct actions. We described a prominent and rapid recruitment of neutrophils to the PLN following vaccination, which was dependent on the secretion of the chemokine CXCL1 and the alarmin molecule IL-1α. In addition, we observed that the initial recruitment occurred mainly via high endothelial venules located in the paracortical and interfollicular regions of the PLN. The analysis of the spatial-temporal patterns of neutrophil migration demonstrated that, in the initial stage, the majority of neutrophils displayed a patrolling behavior, followed by the formation of swarms in the subcapsular sinus of the PLN, which were associated with macrophages in this compartment. Finally, we observed using multiple imaging techniques, that neutrophils phagocytize and transport influenza virus particles. These processes might have important implications in the capacity of these cells to present viral antigens.


Assuntos
Vacinas contra Influenza/imunologia , Neutrófilos/imunologia , Vacinação , Animais , Quimiocina CXCL1/fisiologia , Interleucina-1alfa/fisiologia , Linfonodos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose
10.
Cell Rep ; 26(9): 2307-2315.e5, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30811982

RESUMO

The role of natural killer (NK) cells in the immune response against vaccines is not fully understood. Here, we examine the function of infiltrated NK cells in the initiation of the inflammatory response triggered by inactivated influenza virus vaccine in the draining lymph node (LN). We observed that, following vaccination, NK cells are recruited to the interfollicular and medullary areas of the LN and become activated by type I interferons (IFNs) produced by LN macrophages. The activation of NK cells leads to their early production of IFNγ, which in turn regulates the recruitment of IL-6+ CD11b+ dendritic cells. Finally, we demonstrate that the interleukin-6 (IL-6)-mediated inflammation is important for the development of an effective humoral response against influenza virus in the draining LN.


Assuntos
Imunidade Humoral , Vacinas contra Influenza/imunologia , Interferon gama/metabolismo , Interleucina-6/biossíntese , Células Matadoras Naturais/imunologia , Animais , Células Cultivadas , Feminino , Inflamação/imunologia , Interferon Tipo I/fisiologia , Interleucina-6/fisiologia , Linfonodos/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
11.
Nat Microbiol ; 4(11): 1930-1940, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31358982

RESUMO

The early phase of influenza infection occurs in the upper respiratory tract and the trachea, but little is known about the initial events of virus recognition and control of viral dissemination by the immune system. Here, we report that inflammatory dendritic cells (IDCs) are recruited to the trachea shortly after influenza infection through type I interferon-mediated production of the chemokine CCL2. We further show that recruited IDCs express the C-type lectin receptor SIGN-R1, which mediates direct recognition of the virus by interacting with N-linked glycans present in glycoproteins of the virion envelope. Activation of IDCs via SIGN-R1 triggers the production of the chemokines CCL5, CXCL9 and CXCL10, which initiate the recruitment of protective natural killer (NK) cells in the infected trachea. In the absence of SIGN-R1, the recruitment and activation of NK cells is impaired, leading to uncontrolled viral proliferation. In sum, our results provide insight into the orchestration of the early cellular and molecular events involved in immune protection against influenza.


Assuntos
Moléculas de Adesão Celular/metabolismo , Células Dendríticas/imunologia , Vírus da Influenza A/imunologia , Lectinas Tipo C/metabolismo , Infecções por Orthomyxoviridae/imunologia , Receptores de Superfície Celular/metabolismo , Animais , Quimiocinas/metabolismo , Modelos Animais de Doenças , Cães , Interferon Tipo I/metabolismo , Células Matadoras Naturais , Células Madin Darby de Rim Canino , Camundongos , Infecções por Orthomyxoviridae/virologia , Traqueia/imunologia , Traqueia/virologia
12.
Sci Data ; 5: 180129, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30015806

RESUMO

Recent advances in intravital video microscopy have allowed the visualization of leukocyte behavior in vivo, revealing unprecedented spatiotemporal dynamics of immune cell interaction. However, state-of-the-art software and methods for automatically measuring cell migration exhibit limitations in tracking the position of leukocytes over time. Challenges arise both from the complex migration patterns of these cells and from the experimental artifacts introduced during image acquisition. Additionally, the development of novel tracking tools is hampered by the lack of a sound ground truth for algorithm validation and benchmarking. Therefore, the objective of this work was to create a database, namely LTDB, with a significant number of manually tracked leukocytes. Broad experimental conditions, sites of imaging, types of immune cells and challenging case studies were included to foster the development of robust computer vision techniques for imaging-based immunological research. Lastly, LTDB represents a step towards the unravelling of biological mechanisms by video data mining in systems biology.


Assuntos
Movimento Celular , Bases de Dados Factuais , Microscopia Intravital , Leucócitos/imunologia , Animais , Movimento Celular/imunologia , Quimiotaxia de Leucócito , Interpretação de Imagem Assistida por Computador , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID
13.
Cell Rep ; 18(10): 2427-2440, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28273457

RESUMO

The mechanism by which inflammation influences the adaptive response to vaccines is not fully understood. Here, we examine the role of lymph node macrophages (LNMs) in the induction of the cytokine storm triggered by inactivated influenza virus vaccine. Following vaccination, LNMs undergo inflammasome-independent necrosis-like death that is reliant on MyD88 and Toll-like receptor 7 (TLR7) expression and releases pre-stored interleukin-1α (IL-1α). Furthermore, activated medullary macrophages produce interferon-ß (IFN-ß) that induces the autocrine secretion of IL-1α. We also found that macrophage depletion promotes lymph node-resident dendritic cell (LNDC) relocation and affects the capacity of CD11b+ LNDCs to capture virus and express co-stimulatory molecules. Inhibition of the IL-1α-induced inflammatory cascade reduced B cell responses, while co-administration of recombinant IL-1α increased the humoral response. Stimulation of the IL-1α inflammatory pathway might therefore represent a strategy to enhance antigen presentation by LNDCs and improve the humoral response against influenza vaccines.


Assuntos
Células Dendríticas/imunologia , Inflamação/patologia , Vacinas contra Influenza/imunologia , Linfonodos/imunologia , Macrófagos/patologia , Macrófagos/virologia , Infecções por Orthomyxoviridae/imunologia , Vacinação , Animais , Apresentação de Antígeno/imunologia , Morte Celular , Movimento Celular , Imunidade Humoral , Vacinas contra Influenza/administração & dosagem , Interferon beta/metabolismo , Interleucina-1alfa/metabolismo , Ativação de Macrófagos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Infecções por Orthomyxoviridae/virologia , Receptor 7 Toll-Like/metabolismo , Internalização do Vírus
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