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1.
Platelets ; 32(3): 325-330, 2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33615982

RESUMO

Platelets play an essential role in maintaining vascular integrity after injury. In addition, platelets contribute to the immune response to pathogens. For instance, they express receptors that mediate binding of viruses, and toll-like receptors that activate the cell in response to pathogen-associated molecular patterns. Platelets can be beneficial and/or detrimental during viral infections. They reduce blood-borne viruses by engulfing the free virus and presenting the virus to neutrophils. However, platelets can also enhance inflammation and tissue injury during viral infections. Here, we discuss the roles of platelets in viral infection.


Assuntos
Plaquetas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Neutrófilos/imunologia , Receptores Virais/imunologia , Proteínas Virais/imunologia , Vírus/imunologia , Animais , Plaquetas/patologia , Plaquetas/virologia , /patologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Imunidade Inata , Linfócitos/imunologia , Linfócitos/patologia , Linfócitos/virologia , Neutrófilos/patologia , Neutrófilos/virologia , Ativação Plaquetária/imunologia , Ligação Proteica , Receptores Virais/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Proteínas Virais/genética , Vírus/patogenicidade
2.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530489

RESUMO

Since the first description of nuclear autoantigens in the late 1960s and early 1970s, researchers, including ourselves, have found it difficult to establish monoclonal antibodies (mabs) against nuclear antigens, including the La/SS-B (Sjögrens' syndrome associated antigen B) autoantigen. To date, only a few anti-La mabs have been derived by conventional hybridoma technology; however, those anti-La mabs were not bona fide autoantibodies as they recognize either human La specific, cryptic, or post-translationally modified epitopes which are not accessible on native mouse La protein. Herein, we present a series of novel murine anti-La mabs including truly autoreactive ones. These mabs were elicited from a human La transgenic animal through adoptive transfer of T cells from non-transgenic mice immunized with human La antigen. Detailed epitope and paratope analyses experimentally confirm the hypothesis that somatic hypermutations that occur during T cell dependent maturation can lead to autoreactivity to the nuclear La/SS-B autoantigen.


Assuntos
Autoantígenos/imunologia , Autoimunidade/genética , Linfócitos B/imunologia , Linfócitos B/metabolismo , Comunicação Celular/imunologia , Ribonucleoproteínas/imunologia , Hipermutação Somática de Imunoglobulina , Linfócitos T/imunologia , Células 3T3 , Transferência Adotiva , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos/genética , Autoanticorpos/química , Autoanticorpos/genética , Autoanticorpos/imunologia , Autoantígenos/química , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Modelos Animais de Doenças , Mapeamento de Epitopos , Epitopos/química , Epitopos/imunologia , Imunofluorescência , Células Germinativas/metabolismo , Humanos , Imunização , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Conformação Proteica , Ribonucleoproteínas/química , Linfócitos T/metabolismo
3.
Nat Commun ; 12(1): 792, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542232

RESUMO

The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.


Assuntos
Engenharia Celular/métodos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Proteínas Recombinantes de Fusão/genética , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/patologia , Cultura Primária de Células , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/metabolismo , Biologia Sintética/métodos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440862

RESUMO

Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by the infiltration of exocrine glands including salivary and lachrymal glands responsible for the classical dry eyes and mouth symptoms (sicca syndrome). The spectrum of disease manifestations stretches beyond the classical sicca syndrome with systemic manifestations including arthritis, interstitial lung involvement, and neurological involvement. The pathophysiology underlying SS is not well deciphered, but several converging lines of evidence have supported the conjuncture of different factors interplaying together to foster the initiation and perpetuation of the disease. The innate and adaptive immune system play a cardinal role in this process. In this review, we discuss the inherent parts played by both the innate and adaptive immune system in the pathogenesis of SS.


Assuntos
Imunidade Adaptativa , Suscetibilidade a Doenças/imunologia , Imunidade Inata , Síndrome de Sjogren/imunologia , Animais , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Methods Mol Biol ; 2241: 221-242, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33486740

RESUMO

Mast cells and eosinophils are the key effector cells of allergy [1]. In general, allergic reactions are composed of two phases, namely an early phase and a late phase, and after that resolution occurs. If the allergic reactions fail to resolve after the late phase, allergic inflammation (AI) can evolve into a chronic phase mainly involving mast cells and eosinophils that abundantly coexist in the inflamed tissue in the late and chronic phases and cross-talk in a bidirectional manner. We defined these bidirectional interactions between MCs and Eos, as the "allergic effector unit." This cross talk is mediated by both physical cell-cell contacts through cell surface receptors such as CD48, 2B4, and respective ligands and through released mediators such as various specific granular mediators, arachidonic acid metabolites, cytokines, and chemokines [2, 3]. The allergic effector unit can be studied in vitro in a customized co-culture system using mast cells and eosinophils derived from either mouse or human sources.


Assuntos
Técnicas de Cultura de Células/métodos , Eosinófilos/citologia , Mastócitos/citologia , Animais , Comunicação Celular/imunologia , Comunicação Celular/fisiologia , Quimiocinas/metabolismo , Técnicas de Cocultura/métodos , Citocinas/metabolismo , Eosinófilos/metabolismo , Feminino , Humanos , Hipersensibilidade/metabolismo , Inflamação/metabolismo , Masculino , Mastócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
6.
PLoS One ; 15(9): e0239488, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32946496

RESUMO

The immunopathogenesis of H5N1 virus has been studied intensively since it caused cross-species infection and induced high mortality to human. We previously observed the interaction between monocytes and B cells, which increased the susceptibility of B cell to H5N1 virus infection after a co-culture. Levels of α2,3 sialic acid (avian flu receptor) were also significantly increased on B cell surface in this co-culture model with unclear explanation. In this study, we aimed to determine the possible mechanism that responded for this increase in α2,3 sialic acid on B cells. Acquisition of α2,3 SA by B cells via cell contact-dependent trogocytosis was proposed. Results showed that the lack of α2,3 SA was detected on B cell surface, and B cells acquired membrane-bound α2,3 SA molecules from monocytes in H5N1-infected co-cultures. Occurrence of membrane exchange mainly relied on H5N1 infection and cell-cell contact as opposed to a mock infection and transwell. The increase in α2,3 SA on B cell surface mediated by trogocytosis was associated with the enhanced susceptibility to H5N1 infection. These observations thus provide the evidence that H5N1 influenza virus may utilize trogocytosis to expand its cell tropism and spread to immune cells despite the lack of avian flu receptor.


Assuntos
Linfócitos B/imunologia , Linfócitos B/virologia , Virus da Influenza A Subtipo H5N1/imunologia , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Humana/imunologia , Influenza Humana/virologia , Monócitos/imunologia , Ácido N-Acetilneuramínico/imunologia , Animais , Apresentação do Antígeno , Linfócitos B/metabolismo , Aves , Comunicação Celular/imunologia , Técnicas de Cocultura , Humanos , Influenza Aviária/imunologia , Influenza Aviária/virologia , Monócitos/metabolismo , Monócitos/virologia , Ácido N-Acetilneuramínico/metabolismo , Receptores Virais/imunologia , Receptores Virais/metabolismo
7.
Korean J Parasitol ; 58(3): 217-227, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32615735

RESUMO

Trichomonas vaginalis causes inflammation of the prostate and has been detected in tissues of prostate cancers (PCa), prostatitis and benign prostatic hyperplasia. Obesity is a risk factor for PCa and causes a chronic subclinical inflammation. This chronic inflammation further exacerbates adipose tissue inflammation as results of migration and activation of macrophages. Macrophages are the most abundant immune cells in the PCa microenvironment. M2 macrophages, known as Tumor-Associated Macrophages, are involved in increasing cancer malignancy. In this study, conditioned medium (TCM) of PCa cells infected with live trichomonads contained chemokines that stimulated migration of the mouse preadipocytes (3T3-L1 cells). Conditioned medium of adipocytes incubated with TCM (ATCM) contained Th2 cytokines (IL-4, IL-13). Macrophage migration was stimulated by ATCM. In macrophages treated with ATCM, expression of M2 markers increased, while M1 markers decreased. Therefore, it is suggested that ATCM induces polarization of M0 to M2 macrophages. In addition, conditioned medium from the macrophages incubated with ATCM stimulates the proliferation and invasiveness of PCa. Our findings suggest that interaction between inflamed PCa treated with T. vaginalis and adipocytes causes M2 macrophage polarization, so contributing to the progression of PCa.


Assuntos
Adipócitos/imunologia , Macrófagos/imunologia , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/parasitologia , Trichomonas vaginalis , Animais , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Quimiocinas/imunologia , Inflamação , Masculino , Camundongos , Obesidade , Neoplasias da Próstata/patologia , Fatores de Risco
8.
Nat Commun ; 11(1): 3366, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632165

RESUMO

CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4+ T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bethigh, T-betlow, and T-bet- subsets, with innate, Th1-like effector activity exclusively associated with T-bethigh cells. We further show that the latter population depends on IL-12 produced by CD8α+ type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4+ T lymphocytes. We propose that optimal differentiation of T-bethigh MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Homeostase/imunologia , Memória Imunológica/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-12/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismo
9.
Nat Rev Cancer ; 20(8): 437-454, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32581320

RESUMO

Immunotherapy with checkpoint blockade induces rapid and durable immune control of cancer in some patients and has driven a monumental shift in cancer treatment. Neoantigen-specific CD8+ T cells are at the forefront of current immunotherapy strategies, and the majority of drug discovery and clinical trials revolve around further harnessing these immune effectors. Yet the immune system contains a diverse range of antitumour effector cells, and these must function in a coordinated and synergistic manner to overcome the immune-evasion mechanisms used by tumours and achieve complete control with tumour eradication. A key antitumour effector is the natural killer (NK) cells, cytotoxic innate lymphocytes present at high frequency in the circulatory system and identified by their exquisite ability to spontaneously detect and lyse transformed or stressed cells. Emerging data show a role for intratumoural NK cells in driving immunotherapy response and, accordingly, there have been renewed efforts to further elucidate and target the pathways controlling NK cell antitumour function. In this Review, we discuss recent clinical evidence that NK cells are a key immune constituent in the protective antitumour immune response and highlight the major stages of the cancer-NK cell immunity cycle. We also perform a new analysis of publicly available transcriptomic data to provide an overview of the prognostic value of NK cell gene expression in 25 tumour types. Furthermore, we discuss how the role of NK cells evolves with tumour progression, presenting new opportunities to target NK cell function to enhance cancer immunotherapy response rates across a more diverse range of cancers.


Assuntos
Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Células Matadoras Naturais/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Comunicação Celular/fisiologia , Ciclo Celular/imunologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes cdc/efeitos dos fármacos , Genes cdc/genética , Genes cdc/imunologia , Genes cdc/fisiologia , Humanos , Vigilância Imunológica/imunologia , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Processos Neoplásicos , Prognóstico
10.
Proc Natl Acad Sci U S A ; 117(27): 16072-16082, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571915

RESUMO

The extent to which immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single-cell genomic analyses. These samples were serially obtained from a cohort of advanced gastrointestinal cancer patients enrolled in a trial with chemotherapy and immunotherapy. Using an ecological population model, fitted to clinical tumor burden and immune cell abundance data from each patient, we find evidence of a strong tumor-circulating immune cell interaction in responder patients but not in those patients that progress on treatment. Upon initiation of therapy, immune cell abundance increased rapidly in responsive patients, and once the peak level is reached tumor burden decreases, similar to models of predator-prey interactions; these dynamic patterns were absent in nonresponder patients. To interrogate phenotype dynamics of circulating immune cells, we performed single-cell RNA sequencing at serial time points during treatment. These data show that peripheral immune cell phenotypes were linked to the increased strength of patients' tumor-immune cell interaction, including increased cytotoxic differentiation and strong activation of interferon signaling in peripheral T cells in responder patients. Joint modeling of clinical and genomic data highlights the interactions between tumor and immune cell populations and reveals how variation in patient responsiveness can be explained by differences in peripheral immune cell signaling and differentiation soon after the initiation of immunotherapy.


Assuntos
Comunicação Celular/imunologia , Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Fenótipo , Microambiente Tumoral/imunologia , Regulação da Expressão Gênica , Humanos , Fatores Imunológicos/genética , Fatores Imunológicos/imunologia , Monócitos/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Linfócitos T/imunologia
12.
J Leukoc Biol ; 107(6): 883-892, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32386455

RESUMO

Nonclassical monocytes maintain vascular homeostasis by patrolling the vascular endothelium, responding to inflammatory signals, and scavenging cellular debris. Nonclassical monocytes also prevent metastatic tumor cells from seeding new tissues, but whether the patrolling function of nonclassical monocytes is required for this process is unknown. To answer this question, we utilized an inducible-knockout mouse that exhibits loss of the integrin-adaptor protein Kindlin-3 specifically in nonclassical monocytes. We show that Kindlin-3-deficient nonclassical monocytes are unable to patrol the vascular endothelium in either the lungs or periphery. We also find that Kindlin-3-deficient nonclassical monocytes cannot firmly adhere to, and instead "slip" along, the vascular endothelium. Loss of patrolling activity by nonclassical monocytes was phenocopied by ablation of LFA-1, an integrin-binding partner of Kindlin-3. When B16F10 murine melanoma tumor cells were introduced into Kindlin-3-deficient mice, nonclassical monocytes showed defective patrolling towards tumor cells and failure to ingest tumor particles in vivo. Consequently, we observed a significant, 4-fold increase in lung tumor metastases in mice possessing Kindlin-3-deficient nonclassical monocytes. Thus, we conclude that the patrolling function of nonclassical monocytes is mediated by Kindlin-3 and essential for these cells to maintain vascular endothelial homeostasis and prevent tumor metastasis to the lung.


Assuntos
Proteínas do Citoesqueleto/genética , Regulação Neoplásica da Expressão Gênica , Antígeno-1 Associado à Função Linfocitária/genética , Melanoma Experimental/genética , Monócitos/imunologia , Fagocitose , Neoplasias Cutâneas/genética , Animais , Medula Óssea/imunologia , Transplante de Medula Óssea , Adesão Celular , Comunicação Celular/imunologia , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Feminino , Humanos , Injeções Intravenosas , Pulmão/irrigação sanguínea , Pulmão/imunologia , Pulmão/patologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/secundário , Camundongos , Camundongos Knockout , Monócitos/patologia , Células Neoplásicas Circulantes/imunologia , Células Neoplásicas Circulantes/patologia , Cultura Primária de Células , Transdução de Sinais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Irradiação Corporal Total
13.
Nat Immunol ; 21(7): 766-776, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32424367

RESUMO

Tissue-resident memory T (TRM) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-ß8 endows the bioavailability of transforming growth factor-ß in the microenvironment, thereby promoting the generation of CD8+ TRM cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Diferenciação Celular/imunologia , Memória Imunológica , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Linfócitos T CD8-Positivos/transplante , Coccidiose/imunologia , Coccidiose/parasitologia , Modelos Animais de Doenças , Eimeria/imunologia , Feminino , Humanos , Cadeias beta de Integrinas/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Receptores CXCR3/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante , Fator de Crescimento Transformador beta/metabolismo
14.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188380, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32461135

RESUMO

Cellular communication through gap junctions and hemichannels formed by connexins and through channels made by pannexins allows for metabolic cooperation and control of cellular activity and signalling. These channel proteins have been described to be tumour suppressors that regulate features such as cell death, proliferation and differentiation. However, they display cancer type-dependent and stage-dependent functions and may facilitate tumour progression through junctional and non-junctional pathways. The accumulated knowledge and emerging strategies to target connexins and pannexins are providing novel clinical opportunities for the treatment of cancer. Here, we provide an updated overview of the role of connexins and pannexins in malignant melanoma. We discuss how targeting of these channel proteins may be used to potentiate antitumour effects in therapeutic settings, including through improved immune-mediated tumour elimination.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Conexinas/metabolismo , Melanoma/secundário , Neoplasias Cutâneas/patologia , Pele/patologia , Animais , Antineoplásicos Imunológicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/imunologia , Carcinogênese/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Conexinas/agonistas , Conexinas/antagonistas & inibidores , Modelos Animais de Doenças , Progressão da Doença , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/patologia , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/mortalidade , Microbiota/imunologia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Metástase Neoplásica/imunologia , Metástase Neoplásica/patologia , Metástase Neoplásica/prevenção & controle , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/citologia , Pele/microbiologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
15.
Immunity ; 52(4): 700-715.e6, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32294409

RESUMO

The omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs) that collects peritoneal contaminants and provides a first layer of immunological defense within the abdomen. Here, we investigated the mechanisms that mediate the capture of peritoneal contaminants during peritonitis. Single-cell RNA sequencing and spatial analysis of omental stromal cells revealed that the surface of FALCs were covered by CXCL1+ mesothelial cells, which we termed FALC cover cells. Blockade of CXCL1 inhibited the recruitment and aggregation of neutrophils at FALCs during zymosan-induced peritonitis. Inhibition of protein arginine deiminase 4, an enzyme important for the release of neutrophil extracellular traps, abolished neutrophil aggregation and the capture of peritoneal contaminants by omental FALCs. Analysis of omental samples from patients with acute appendicitis confirmed neutrophil recruitment and bacterial capture at FALCs. Thus, specialized omental mesothelial cells coordinate the recruitment and aggregation of neutrophils to capture peritoneal contaminants.


Assuntos
Apendicite/imunologia , Linfócitos/imunologia , Neutrófilos/imunologia , Omento/imunologia , Peritonite/imunologia , Células Estromais/imunologia , Doença Aguda , Animais , Apendicite/genética , Apendicite/microbiologia , Comunicação Celular/imunologia , Quimiocina CXCL1/genética , Quimiocina CXCL1/imunologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Epitélio/imunologia , Epitélio/microbiologia , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/patogenicidade , Armadilhas Extracelulares/imunologia , Feminino , Expressão Gênica , Humanos , Linfócitos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos , Neutrófilos/microbiologia , Omento/microbiologia , Peritonite/induzido quimicamente , Peritonite/genética , Peritonite/microbiologia , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Células Estromais/microbiologia , Técnicas de Cultura de Tecidos , Zimosan/administração & dosagem
16.
J Leukoc Biol ; 107(6): 917-932, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32272497

RESUMO

T cells are crucial for the success of immune-based cancer therapy. Reinvigorating antitumor T cell activity by blocking checkpoint inhibitory receptors has provided clinical benefits for many cancer patients. However, the efficacy of these treatments varies in cancer patients and the mechanisms underlying these diverse responses remain elusive. The density and status of tumor-infiltrating T cells have been shown to positively correlate with patient response to checkpoint blockades. Therefore, further understanding of the heterogeneity, clonal expansion, migration, and effector functions of tumor-infiltrating T cells will provide fundamental insights into antitumor immune responses. To this end, recent advances in single-cell RNA sequencing technology have enabled profound and extensive characterization of intratumoral immune cells and have improved our understanding of their dynamic relationships. Here, we summarize recent progress in single-cell RNA sequencing technology and current strategies to uncover heterogeneous tumor-infiltrating T cell subsets. In particular, we discuss how the coupling of deep transcriptome information with T cell receptor (TCR)-based lineage tracing has furthered our understanding of intratumoral T cell populations. We also discuss the functional implications of various T cell subsets in tumors and highlight the identification of novel T cell markers with therapeutic or prognostic potential.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , RNA Neoplásico/genética , Subpopulações de Linfócitos T/imunologia , Transcriptoma , Comunicação Celular/genética , Comunicação Celular/imunologia , Expressão Gênica , Heterogeneidade Genética , Humanos , Ativação Linfocitária , Linfócitos do Interstício Tumoral/patologia , Neoplasias/genética , Neoplasias/patologia , RNA Neoplásico/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Sequência de RNA , Análise de Célula Única , Subpopulações de Linfócitos T/classificação , Subpopulações de Linfócitos T/patologia , Microambiente Tumoral/imunologia
17.
Nat Med ; 26(4): 511-518, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251406

RESUMO

Cellular immunity is critical for controlling intracellular pathogens, but individual cellular dynamics and cell-cell cooperativity in evolving human immune responses remain poorly understood. Single-cell RNA-sequencing (scRNA-seq) represents a powerful tool for dissecting complex multicellular behaviors in health and disease1,2 and nominating testable therapeutic targets3. Its application to longitudinal samples could afford an opportunity to uncover cellular factors associated with the evolution of disease progression without potentially confounding inter-individual variability4. Here, we present an experimental and computational methodology that uses scRNA-seq to characterize dynamic cellular programs and their molecular drivers, and apply it to HIV infection. By performing scRNA-seq on peripheral blood mononuclear cells from four untreated individuals before and longitudinally during acute infection5, we were powered within each to discover gene response modules that vary by time and cell subset. Beyond previously unappreciated individual- and cell-type-specific interferon-stimulated gene upregulation, we describe temporally aligned gene expression responses obscured in bulk analyses, including those involved in proinflammatory T cell differentiation, prolonged monocyte major histocompatibility complex II upregulation and persistent natural killer (NK) cell cytolytic killing. We further identify response features arising in the first weeks of infection, for example proliferating natural killer cells, which potentially may associate with future viral control. Overall, our approach provides a unified framework for characterizing multiple dynamic cellular responses and their coordination.


Assuntos
Comunicação Celular , Infecções por HIV/genética , Infecções por HIV/imunologia , Imunidade Celular/fisiologia , Análise de Célula Única/métodos , Doença Aguda , Reação de Fase Aguda/genética , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/patologia , Adolescente , Adulto , Comunicação Celular/genética , Comunicação Celular/imunologia , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/imunologia , Infecções por HIV/patologia , HIV-1/genética , HIV-1/patogenicidade , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Estudos Longitudinais , Análise de Sequência de RNA/métodos , Integração de Sistemas , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Carga Viral/genética , Carga Viral/imunologia , Adulto Jovem
18.
Mol Immunol ; 121: 167-185, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32229377

RESUMO

Some studies have shown that maturation of dendritic cells (DCs) is modulated directly by pathogen components via pattern recognition receptors such as Toll-like receptors, but also by signal like CD40 ligand (CD40 L or CD154) mediated by activated T cells. Several reports indicate that invariant natural killer T (iNKT) cells up-regulate CD40 L upon stimulation and thereby induce activation and maturation of DCs through crosslink with CD40. Our previous findings indicated that iNKT cells promote Th2 cell responses through the induction of immunogenic maturation of lung DCs (LDCs) in the asthmatic murine, but its mechanism remains unclear. Therefore, we investigated the immunomodulatory effects of blockade of CD40 L using anti-CD40 L treatment on Th2 cell responses and immunogenic maturation of LDCs, and further analyzed whether these influences of blockade of CD40 L were related to lung iNKT cells using iNKT cell-deficient mice and the combination treatment of specific iNKT cell activation with anti-CD40 L treatment in murine models of asthma. Our findings showed that blockade of CD40 L using anti-CD40 L treatment attenuated Th2 cell responses in wild-type (WT) mice, but not in CD1d-deficient mice sensitized and challenged with ovalbumin (OVA) or house dust mite (HDM). Meanwhile, blockade of CD40 L down-regulated immunogenic maturation of LDCs in WT mice, but not in CD1d-deficient mice sensitized and challenged with OVA. Additionally, agonistic anti-CD40 treatment reversed the inhibitory effects of anti-CD40 L treatment on Th2 cell responses and LDC activation in an OVA-induced mouse model of asthma. Furthermore, LDCs from asthmatic mice treated with anti-CD40 L could significantly reduce the influence on Th2 cell responses in vivo and in vitro. Finally, α-Galactosylceramide plus anti-CD40 L treatment stimulated lung iNKT cells, but suppressed Th2 cell responses in the asthmatic mice. Taken together, our data raise an evidence that blockade of CD40 L attenuates Th2 cell responses through the inhibition of immunogenic maturation of LDCs, which may be at least partially related to lung iNKT cells in murine models of asthma.


Assuntos
Asma/tratamento farmacológico , Ligante de CD40/antagonistas & inibidores , Células Dendríticas/imunologia , Células T Matadoras Naturais/efeitos dos fármacos , Células Th2/imunologia , Animais , Antígenos CD1d/genética , Asma/imunologia , Asma/patologia , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Comunicação Celular/imunologia , Modelos Animais de Doenças , Feminino , Galactosilceramidas/administração & dosagem , Humanos , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Ovalbumina/imunologia , Pyroglyphidae/imunologia
19.
Int J Mol Sci ; 21(4)2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32098106

RESUMO

All B cell leukaemias and a substantial fraction of lymphomas display a natural niche residency in the bone marrow. While the bone marrow compartment may only be one of several sites of disease manifestations, the strong clinical significance of minimal residual disease (MRD) in the bone marrow strongly suggests that privileged niches exist in this anatomical site favouring central elements of malignant transformation. Here, the co-existence of two hierarchical systems, originating from haematopoietic and mesenchymal stem cells, has extensively been characterised with regard to regulation of the former (blood production) by the latter. How these two systems cooperate under pathological conditions is far less understood and is the focus of many current investigations. More recent single-cell sequencing techniques have now identified an unappreciated cellular heterogeneity of the bone marrow microenvironment. How each of these cell subtypes interact with each other and regulate normal and malignant haematopoiesis remains to be investigated. Here we review the evidences of how bone marrow stroma cells and malignant B cells reciprocally interact. Evidently from published data, these cell-cell interactions induce profound changes in signalling, gene expression and metabolic adaptations. While the past research has largely focussed on understanding changes imposed by stroma- on tumour cells, it is now clear that tumour-cell contact also has fundamental ramifications for the biology of stroma cells. Their careful characterisations are not only interesting from a scientific biological viewpoint but also relevant to clinical practice: Since tumour cells heavily depend on stroma cells for cell survival, proliferation and dissemination, interference with bone marrow stroma-tumour interactions bear therapeutic potential. The molecular characterisation of tumour-stroma interactions can identify new vulnerabilities, which could be therapeutically exploited.


Assuntos
Comunicação Celular/imunologia , Células-Tronco Hematopoéticas/imunologia , Leucemia de Células B/imunologia , Células-Tronco Mesenquimais/imunologia , Microambiente Tumoral/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia de Células B/patologia , Células-Tronco Mesenquimais/patologia , Células Estromais/imunologia , Células Estromais/patologia
20.
J Pathol ; 250(5): 656-666, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32086805

RESUMO

The cells of the mononuclear phagocyte system (MPS) constitute a dispersed organ, which is distributed throughout the body. Macrophages in different tissues display distinctive mosaic phenotypes as resident and recruited cells of embryonic and bone marrow origin, respectively. They help to maintain homeostasis during development and throughout adult life, yet contribute to the pathogenesis of many disease processes, including inflammation, innate and adaptive immunity, metabolic disorders, and cancer. Heterogeneous tissue macrophage populations display a wide variety of surface molecules to recognise and respond to host, microbial, and exogenous ligands in their environment; their receptors mediate the uptake and destruction of effete and dying host cells and pathogens, as well as contribute trophic and secretory functions within every organ in the body. Apart from local cellular interactions, macrophage surface molecules and products serve to mobilise and coordinate systemic humoral and cellular responses. Their use as antigen markers in pathogenesis and as potential drug targets has lagged in clinical pathology and human immunotherapy. In this review, we summarise the properties of selected surface molecules expressed on macrophages in different tissues and disease processes, to provide a functional basis for diagnosis, further research, and treatment. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Imunidade Adaptativa/imunologia , Membrana Celular/patologia , Inflamação/patologia , Macrófagos/patologia , Receptores de Superfície Celular/metabolismo , Animais , Comunicação Celular/imunologia , Membrana Celular/imunologia , Humanos , Inflamação/imunologia , Macrófagos/imunologia , Receptores de Superfície Celular/imunologia
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