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1.
Nat Immunol ; 22(10): 1210-1217, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34545250

RESUMO

When helper T (TH) cell polarization was initially described three decades ago, the TH cell universe grew dramatically. New subsets were described based on their expression of few specific cytokines. Beyond TH1 and TH2 cells, this led to the coining of various TH17 and regulatory (Treg) cell subsets as well as TH22, TH25, follicular helper (TFH), TH3, TH5 and TH9 cells. High-dimensional single-cell analysis revealed that a categorization of TH cells into a single-cytokine-based nomenclature fails to capture the complexity and diversity of TH cells. Similar to the simple nomenclature used to describe innate lymphoid cells (ILCs), we propose that TH cell polarization should be categorized in terms of the help they provide to phagocytes (type 1), to B cells, eosinophils and mast cells (type 2) and to non-immune tissue cells, including the stroma and epithelium (type 3). Studying TH cells based on their helper function and the cells they help, rather than phenotypic features such as individual analyzed cytokines or transcription factors, better captures TH cell plasticity and conversion as well as the breadth of immune responses in vivo.


Assuntos
Citocinas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Linfócitos B/imunologia , Plasticidade Celular/imunologia , Eosinófilos/imunologia , Epitélio/imunologia , Humanos , Imunidade Inata/imunologia , Linfócitos/imunologia , Fagócitos/imunologia
2.
Nat Immunol ; 22(9): 1140-1151, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426691

RESUMO

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
3.
Sci Immunol ; 6(62)2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376481

RESUMO

To understand how a protective immune response against SARS-CoV-2 develops over time, we integrated phenotypic, transcriptional and repertoire analyses on PBMCs from mild and severe COVID-19 patients during and after infection, and compared them to healthy donors (HD). A type I IFN-response signature marked all the immune populations from severe patients during the infection. Humoral immunity was dominated by IgG production primarily against the RBD and N proteins, with neutralizing antibody titers increasing post infection and with disease severity. Memory B cells, including an atypical FCRL5+ T-BET+ memory subset, increased during the infection, especially in patients with mild disease. A significant reduction of effector memory, CD8+ T cells frequency characterized patients with severe disease. Despite such impairment, we observed robust clonal expansion of CD8+ T lymphocytes, while CD4+ T cells were less expanded and skewed toward TCM and TH2-like phenotypes. MAIT cells were also expanded, but only in patients with mild disease. Terminally differentiated CD8+ GZMB+ effector cells were clonally expanded both during the infection and post-infection, while CD8+ GZMK+ lymphocytes were more expanded post-infection and represented bona fide memory precursor effector cells. TCR repertoire analysis revealed that only highly proliferating T cell clonotypes, which included SARS-CoV-2-specific cells, were maintained post-infection and shared between the CD8+ GZMB+ and GZMK+ subsets. Overall, this study describes the development of immunity against SARS-CoV-2 and identifies an effector CD8+ T cell population with memory precursor-like features.


Assuntos
COVID-19/genética , COVID-19/imunologia , Interações Hospedeiro-Patógeno/imunologia , Imunofenotipagem , SARS-CoV-2/imunologia , Transcriptoma , Adulto , Idoso , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , COVID-19/virologia , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Evolução Clonal/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Isotipos de Imunoglobulinas/imunologia , Memória Imunológica , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
4.
Mol Immunol ; 136: 138-149, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34146759

RESUMO

Gamma-delta (γδ) T cells are a heterogeneous population of immune cells, which constitute <5% of total T cells in mice lymphoid tissue and human peripheral blood. However, they comprise a higher proportion of T cells in the epithelial and mucosal barrier, where they perform immune functions, help in tissue repair, and maintaining homeostasis. These tissues resident γδ T cells possess properties of innate and adaptive immune cells which enables them to perform a variety of functions during homeostasis and disease. Emerging data suggest the involvement of γδ T cells during transplant rejection and survival. Interestingly, several functions of γδ T cells can be modulated through their interaction with other immune cells. This review provides an overview of development, differentiation plasticity into regulatory and effector phenotypes of γδ T cells during homeostasis and various diseases.


Assuntos
Rejeição de Enxerto/imunologia , Tolerância Imunológica/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa/imunologia , Animais , Plasticidade Celular/imunologia , Humanos , Imunidade Inata/imunologia , Camundongos , Linfócitos T/citologia
5.
Front Immunol ; 12: 652488, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084163

RESUMO

Background: Excessive alcohol intake is associated with adverse immune response-related effects, however, acute and chronic abuse differently modulate monocyte activation. In this study, we have evaluated the phenotypic and functional changes of monocytes in acutely intoxicated healthy volunteers (HV). Methods: Twenty-two HV consumed individually adjusted amounts of alcoholic beverages until reaching a blood alcohol level of 1‰ after 4h (T4). Peripheral blood was withdrawn before and 2h (T2), 4h (T4), 6h (T6), 24h (T24), and 48h (T48) after starting the experiment and stained for CD14, CD16 and TLR4. CD14brightCD16-, CD14brightCD16+ and CD14dimCD16+ monocyte subsets and their TLR4 expression were analyzed by flow cytometry. Inflammasome activation via caspase-1 in CD14+ monocytes was measured upon an ex vivo in vitro LPS stimulation. Systemic IL-1ß and adhesion capacity of isolated CD14+ monocytes upon LPS stimulation were evaluated. Results: The percentage of CD14+ monocyte did not change following alcohol intoxication, whereas CD14brightCD16- monocyte subset significantly increased at T2 and T24, CD14brightCD16+ at T2, T4 and T6 and CD14dimCD16+ at T4 and T6. The relative fraction of TLR4 expressing CD14+ monocytes as well as the density of TLR4 surface presentation increased at T2 and decreased at T48 significantly. TLR4+CD14+ monocytes were significantly enhanced in all subsets at T2. TLR4 expression significantly decreased in CD14brightCD16- at T48, in CD14brightCD16+ at T24 and T48, increased in CD14dimCD16+ at T2. IL-1ß release upon LPS stimulation decreased at T48, correlating with TLR4 receptor expression. Alcohol downregulated inflammasome activation following ex vivo in vitro stimulation with LPS between T2 and T48 vs. T0. The adhesion capacity of CD14+ monocytes decreased from T2 with significance at T4, T6 and T48. Following LPS administration, a significant reduction of adhesion was observed at T4 and T6. Conclusions: Alcohol intoxication immediately redistributes monocyte subsets toward the pro-inflammatory phenotype with their subsequent differentiation into the anti-inflammatory phenotype. This is paralleled by a significant functional depression, suggesting an alcohol-induced time-dependent hyporesponsiveness of monocytes to pathogenic triggers.


Assuntos
Intoxicação Alcoólica/imunologia , Intoxicação Alcoólica/metabolismo , Plasticidade Celular , Monócitos/imunologia , Monócitos/metabolismo , Adolescente , Adulto , Biomarcadores , Plasticidade Celular/imunologia , Voluntários Saudáveis , Humanos , Imunofenotipagem , Interleucina-1beta/metabolismo , Pessoa de Meia-Idade , Fatores de Tempo , Receptor 4 Toll-Like/metabolismo , Adulto Jovem
6.
Front Immunol ; 12: 658681, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093546

RESUMO

Fusobacterium nucleatum (Fn) has been considered as a significant contributor in promoting colorectal carcinoma (CRC) development by suppressing host anti-tumor immunity. Recent studies demonstrated that the aggregation of M2 macrophage (Mφ) was involved in CRC progress driven by Fn infection. However, the underlying molecular mechanisms are poorly characterized. Here, we investigated the role of Fn in Mφ polarization as well as its effect on CRC malignancy. Fn infection facilitated differentiation of Mφ into the M2-like Mφ phenotype by in vitro study. Histological observation from Fn-positive CRC tissues confirmed the abundance of tumor-infiltrating M2-like Mφ. Fn-induced M2-like Mφ polarization was weakened once inhibiting a highly expressed damage-associated molecular pattern (DAMP) molecule S100A9 mainly derived from Fn-challenged Mφ and CRC cells. In addition, Fn-challenged M2-like Mφ conferred CRC cells a more malignant phenotype, showing stronger proliferation and migration characteristics in vitro and significantly enhanced tumor growth in vivo, all of which were partially inhibited when S100A9 was lost. Mechanistic studies further demonstrated that activation of TLR4/NF-κB signaling pathway mediated Fn-induced S100A9 expression and subsequent M2-like Mφ activation. Collectively, these findings indicate that elevated S100A9 in Fn-infected CRC microenvironment participates in M2-like Mφ polarization, thereby facilitating CRC malignancy. Furthermore, targeting TLR4/NF-κB/S100A9 cascade may serve as promising immunotherapeutic strategy for Fn-associated CRC.


Assuntos
Calgranulina B/metabolismo , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/imunologia , Plasticidade Celular/imunologia , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Infecções por Fusobacterium/imunologia , Infecções por Fusobacterium/microbiologia , Fusobacterium nucleatum/imunologia , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Transdução de Sinais , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
7.
Front Immunol ; 12: 616309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968018

RESUMO

Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (TEM) cells, central memory T (TCM) cells, and tissue-resident memory T (TRM) cells have been identified. The most recently identified subset, TRM cells, is characterized by the expression of the C-type lectin CD69 and/or the integrin CD103. TRM cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, TRM cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8+ TRM cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4+ TRM cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4+ TRM cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4+ TRM cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4+ TRM cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Imunidade nas Mucosas , Memória Imunológica , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Plasticidade Celular/imunologia , Suscetibilidade a Doenças , Epigênese Genética , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Especificidade de Órgãos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
8.
Nat Immunol ; 22(6): 687-698, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33986548

RESUMO

The aged adaptive immune system is characterized by progressive dysfunction as well as increased autoimmunity. This decline is responsible for elevated susceptibility to infection and cancer, as well as decreased vaccination efficacy. Recent evidence indicates that CD4+ T cell-intrinsic alteratins contribute to chronic inflammation and are sufficient to accelerate an organism-wide aging phenotype, supporting the idea that T cell aging plays a major role in body-wide deterioration. In this Review, we propose ten molecular hallmarks to represent common denominators of T cell aging. These hallmarks are grouped into four primary hallmarks (thymic involution, mitochondrial dysfunction, genetic and epigenetic alterations, and loss of proteostasis) and four secondary hallmarks (reduction of the TCR repertoire, naive-memory imbalance, T cell senescence, and lack of effector plasticity), and together they explain the manifestation of the two integrative hallmarks (immunodeficiency and inflammaging). A major challenge now is weighing the relative impact of these hallmarks on T cell aging and understanding their interconnections, with the final goal of defining molecular targets for interventions in the aging process.


Assuntos
Envelhecimento/imunologia , Imunidade Celular , Linfócitos T/imunologia , Envelhecimento/genética , Autoimunidade/genética , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Suscetibilidade a Doenças/imunologia , Epigênese Genética/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Proteostase/genética , Proteostase/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Timo/imunologia , Timo/fisiopatologia
9.
Front Immunol ; 12: 659151, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868306

RESUMO

Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and cellular dynamics governing humoral immunity. In this review, we highlight advances that demonstrate that fundamental GC B cell function, selection, proliferation and SHM occur within distinct cell states. The resulting new model provides new opportunities to understand the evolution of immunity in infectious, autoimmune and neoplastic diseases.


Assuntos
Centro Germinativo/citologia , Centro Germinativo/fisiologia , Animais , Formação de Anticorpos , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Humanos , Imunidade Humoral , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia
10.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925531

RESUMO

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in nTregs derived from wild-type (WT) and CD8-deficient mice (CD8-/-), with increased IL-6 levels in nTregs from CD8-/- mice in comparison to WT nTregs. Thus, identification of the molecular mechanisms regulating IL-6 production is critical to understanding the phenotypic plasticity of nTregs. Electrophoretic mobility shift assays (EMSA) were performed to determine transcription factor binding to four Il-6 promoter loci using nuclear extracts from nTregs of WT and CD8-/- mice. Increased transcription factor binding for each of the Il-6 loci was identified in CD8-/- compared to WT nTregs. The impact of transcription factor binding and a novel short tandem repeat (STR) on Il-6 promoter activity was analyzed by luciferase reporter assays. The Il-6 promoter regions closer to the transcription start site (TSS) were more relevant to the regulation of Il-6 depending on NF-κB, c-Fos, and SP and USF family members. Two Il-6 promoter loci were most critical for the inducibility by lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα). A novel STR of variable length in the Il-6 promoter was identified with diverging prevalence in nTregs from WT or CD8-/- mice. The predominant GT repeat in CD8-/- nTregs revealed the highest luciferase activity. These novel regulatory mechanisms controlling the transcriptional regulation of the Il-6 promoter are proposed to contribute to nTregs plasticity and may be central to disease pathogenesis.


Assuntos
Hipersensibilidade/imunologia , Interleucina-6/imunologia , Pneumopatias/imunologia , Linfócitos T Reguladores/metabolismo , Adaptação Fisiológica/imunologia , Animais , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Citocinas/imunologia , Interleucina-10/imunologia , Interleucina-6/genética , Pneumopatias/genética , Pneumopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Regiões Promotoras Genéticas , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/metabolismo
11.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33755719

RESUMO

In response to infection, T cells adopt a range of differentiation states, creating numerous heterogeneous subsets that exhibit different phenotypes, functions, and migration patterns. This T cell heterogeneity is a universal feature of T cell immunity, needed to effectively control pathogens in a context-dependent manner and generate long-lived immunity to those pathogens. Here, we review new insights into differentiation state dynamics and population heterogeneity of CD8+ T cells in acute and chronic viral infections and cancer and highlight the parallels and distinctions between acute and chronic antigen stimulation settings. We focus on transcriptional and epigenetic networks that modulate the plasticity and terminal differentiation of antigen-specific CD8+ T cells and generate functionally diverse T cell subsets with different roles to combat infection and cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Neoplasias/imunologia , Viroses/imunologia , Vírus/imunologia , Doença Aguda , Animais , Antígenos Virais/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Doença Crônica , Epigênese Genética , Humanos , Viroses/virologia
13.
J Immunol Res ; 2021: 8816041, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33553436

RESUMO

Autoimmune diseases (such as rheumatoid arthritis, asthma, autoimmune bowel disease) are a complex disease. Improper activation of the immune system or imbalance of immune cells can cause the immune system to transform into a proinflammatory state, leading to autoimmune pathological damage. Recent studies have shown that autoimmune diseases are closely related to CD4+ T helper cells (Th). The original CD4 T cells will differentiate into different T helper (Th) subgroups after activation. According to their cytokines, the types of Th cells are different to produce lineage-specific cytokines, which play a role in autoimmune homeostasis. When Th differentiation and its cytokines are not regulated, it will induce autoimmune inflammation. Autoimmune bowel disease (IBD) is an autoimmune disease of unknown cause. Current research shows that its pathogenesis is closely related to Th17 cells. This article reviews the role and plasticity of the upstream and downstream cytokines and signaling pathways of Th17 cells in the occurrence and development of autoimmune bowel disease and summarizes the new progress of IBD immunotherapy.


Assuntos
Suscetibilidade a Doenças , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Animais , Biomarcadores , Plasticidade Celular/imunologia , Citocinas/metabolismo , Gerenciamento Clínico , Humanos , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/patologia , Doenças Inflamatórias Intestinais/terapia , Microbiota , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
14.
Mol Cancer ; 20(1): 24, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33522932

RESUMO

Noncoding RNA (ncRNA) transcripts that did not code proteins but regulate their functions were extensively studied for the last two decades and the plethora of discoveries have instigated scientists to investigate their dynamic roles in several diseases especially in cancer. However, there is much more to learn about the role of ncRNAs as drivers of malignant cell evolution in relation to macrophage polarization in the tumor microenvironment. At the initial stage of tumor development, macrophages have an important role in directing Go/No-go decisions to the promotion of tumor growth, immunosuppression, and angiogenesis. Tumor-associated macrophages behave differently as they are predominantly induced to be polarized into M2, a pro-tumorigenic type when recruited with the tumor tissue and thereby favoring the tumorigenesis. Polarization of macrophages into M1 or M2 subtypes plays a vital role in regulating tumor progression, metastasis, and clinical outcome, highlighting the importance of studying the factors driving this process. A substantial number of studies have demonstrated that ncRNAs are involved in the macrophage polarization based on their ability to drive M1 or M2 polarization and in this review we have described their functions and categorized them into oncogenes, tumor suppressors, Juggling tumor suppressors, and Juggling oncogenes.


Assuntos
Biomarcadores Tumorais , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , RNA não Traduzido/genética , Animais , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , MicroRNAs/genética , Terapia de Alvo Molecular , Neoplasias/patologia , Neoplasias/terapia , RNA Longo não Codificante , Microambiente Tumoral
15.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33533916

RESUMO

Several studies have analyzed antiviral immune pathways in late-stage severe COVID-19. However, the initial steps of SARS-CoV-2 antiviral immunity are poorly understood. Here we have isolated primary SARS-CoV-2 viral strains and studied their interaction with human plasmacytoid predendritic cells (pDCs), a key player in antiviral immunity. We show that pDCs are not productively infected by SARS-CoV-2. However, they efficiently diversified into activated P1-, P2-, and P3-pDC effector subsets in response to viral stimulation. They expressed CD80, CD86, CCR7, and OX40 ligand at levels similar to influenza virus-induced activation. They rapidly produced high levels of interferon-α, interferon-λ1, IL-6, IP-10, and IL-8. All major aspects of SARS-CoV-2-induced pDC activation were inhibited by hydroxychloroquine. Mechanistically, SARS-CoV-2-induced pDC activation critically depended on IRAK4 and UNC93B1, as established using pDC from genetically deficient patients. Overall, our data indicate that human pDC are efficiently activated by SARS-CoV-2 particles and may thus contribute to type I IFN-dependent immunity against SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , COVID-19/metabolismo , Plasticidade Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , SARS-CoV-2/imunologia , Biomarcadores , COVID-19/tratamento farmacológico , COVID-19/virologia , Citocinas/metabolismo , Células Dendríticas/virologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunomodulação , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Interferon Tipo I/metabolismo , Interferons/metabolismo
16.
Oncol Rep ; 45(3): 879-890, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33469682

RESUMO

Waterpipe tobacco smoking (WPS) continues to spread globally and presents serious health hazards. The aim of the present study was to investigate the effects of treatment with WPS condensate (WPSC) on lung cell proliferation and plasticity as well as tumor cell recognition and killing by natural killer (NK) cells using cytotoxicity assays. The results indicated that exposure of normal and cancer lung cell lines to WPSC resulted in a decrease in their in vitro growth in a dose-dependent manner and it induced tumor senescence. In addition, WPSC selectively caused DNA damage as revealed by an increase in γH2AX and 53BP1 in tumor lung cells. To gain further insight into the molecular mechanisms altered by WPSC, we conducted a global comprehensive transcriptome analysis of WPSC-treated tumor cells. Data analysis identified an expression profile of genes that best distinguished treated and non-treated cells involving several pathways. Of these pathways, we focused on those involved in epithelial to mesenchymal transition (EMT) and stemness. Results showed that WPSC induced an increase in SNAI2 expression associated with EMT, ACTA2 and SERPINE2 were involved in invasion and CD44 was associated with stemness. Furthermore, WPSC exposure increased the expression of inflammatory response genes including CASP1, IL1B, IL6 and CCL2. While immune synapse formation between NK and WPSC-treated lung cancer target cells was not affected, the capacity of NK cells to kill these target cells was reduced. The data reported in the present study are, to the best of our knowledge, the first in vitro demonstration of WPSC effects on lung cellular parameters providing evidence of its potential involvement in tumor physiology and development.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Fumaça/efeitos adversos , Tabaco/efeitos adversos , Fumar Cachimbo de Água/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Plasticidade Celular/efeitos dos fármacos , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Dano ao DNA/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia
17.
Infect Immun ; 89(4)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33495271

RESUMO

Elderly individuals are at increased risk of life-threatening pulmonary infections. Neutrophils are a key determinant of the disease course of pathogen-induced pneumonia. Optimal host defense balances initial robust pulmonary neutrophil responses to control pathogen numbers, ultimately followed by the resolution of inflammation to prevent pulmonary damage. Recent evidence suggests that phenotypic and functional heterogeneity in neutrophils impacts host resistance to pulmonary pathogens. Apart from their apparent role in innate immunity, neutrophils also orchestrate subsequent adaptive immune responses during infection. Thus, the outcome of pulmonary infections can be shaped by neutrophils. This review summarizes the age-driven impairment of neutrophil responses and the contribution of these cells to the susceptibility of the elderly to pneumonia. We describe how aging is accompanied by changes in neutrophil recruitment, resolution, and function. We discuss how systemic and local changes alter the neutrophil phenotype in aged hosts. We highlight the gap in knowledge of whether these changes in neutrophils also contribute to the decline in adaptive immunity seen with age. We further detail the factors that drive dysregulated neutrophil responses in the elderly and the pathways that may be targeted to rebalance neutrophil activity and boost host resistance to pulmonary infections.


Assuntos
Envelhecimento/imunologia , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno , Neutrófilos/imunologia , Neutrófilos/metabolismo , Pneumonia/etiologia , Imunidade Adaptativa , Fatores Etários , Envelhecimento/metabolismo , Animais , Comunicação Celular/imunologia , Plasticidade Celular/imunologia , Citocinas/metabolismo , Gerenciamento Clínico , Resistência à Doença/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Ativação de Neutrófilo/genética , Ativação de Neutrófilo/imunologia , Fagocitose/genética , Fagocitose/imunologia , Pneumonia/metabolismo , Pneumonia/prevenção & controle , Pneumonia/terapia
18.
Int J Mol Sci ; 22(2)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477945

RESUMO

Macrophages are prominent cells in normally healing adult skin wounds, yet their exact functions and functional significance to healing outcomes remain enigmatic. Many functional attributes are ascribed to wound macrophages, including host defense and support of the proliferation of new tissue to replace that lost by injury. Indeed, the depletion of macrophages is unmistakably detrimental to normal skin healing in adult mammals. Yet in certain systems, dermal wounds seem to heal well with limited or even no functional macrophages, creating an apparent paradox regarding the function of this cell in wounds. Recent advances in our understanding of wound macrophage phenotypes, along with new information about cellular plasticity in wounds, may provide some explanation for the apparently contradictory findings and suggest new paradigms regarding macrophage function in wounds. Continued study of this remarkable cell is needed to develop effective therapeutic options to improve healing outcomes.


Assuntos
Macrófagos/fisiologia , Cicatrização/fisiologia , Adulto , Animais , Plasticidade Celular/imunologia , Plasticidade Celular/fisiologia , Humanos , Inflamação/etiologia , Inflamação/patologia , Mamíferos , Pele/imunologia , Pele/patologia , Pele/fisiopatologia
19.
J Mol Biol ; 433(1): 166607, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-32755620

RESUMO

B lymphocytes play a central role in host immunity. They orchestrate humoral immune responses that modulate activities of other immune cells and produce neutralizing antibodies that confer lasting immunity to infectious diseases including smallpox, measles and poliomyelitis. In addition to these traditional functions is the recent recognition that B cells also play critical role in maintaining peripheral tolerance and suppressing the development or severity of autoimmune diseases. Their immune suppressive function is attributed to relatively rare populations of regulatory B cells (Bregs) that produce anti-inflammatory cytokines including interleukin 10 (IL-10), IL-35 and transforming growth factor-ß. The IL-35-producing B cell (i35-Breg) is the newest Breg subset described. i35-Bregs suppress central nervous system autoimmune diseases by inducing infectious tolerance whereby conventional B cells acquire regulatory functions that suppress pathogenic Th17 responses. In this review, we discuss immunobiology of i35-Breg cell, i35-Breg therapies for autoimmune diseases and potential therapeutic strategies for depleting i35-Bregs that suppress immune responses against pathogens and tumor cells.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B Reguladores/imunologia , Linfócitos B Reguladores/metabolismo , Interleucinas/metabolismo , Animais , Plasticidade Celular/imunologia , Citocinas/genética , Citocinas/metabolismo , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/terapia , Imunomodulação , Imunoterapia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
20.
J Allergy Clin Immunol ; 148(1): 209-224.e9, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33309741

RESUMO

BACKGROUND: Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent. OBJECTIVE: We sought to investigate the role of CYLD in Treg cell function and TH2 cell immune responses under steady-state conditions and during helminth infection. METHODS: Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays. RESULTS: Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation. CONCLUSIONS: Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into TH2 cell-like effector cells, which potentiates parasite resistance.


Assuntos
Plasticidade Celular/imunologia , Enzima Desubiquitinante CYLD/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Imunidade/imunologia , Linfócitos T Reguladores/imunologia , Animais , Inflamação/imunologia , Interleucina-4/imunologia , MAP Quinase Quinase Quinases/imunologia , Camundongos , Camundongos Knockout , NF-kappa B/imunologia , Nippostrongylus/imunologia , Transdução de Sinais/imunologia , Células Th2/imunologia , Regulação para Cima/imunologia
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