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1.
Nat Commun ; 12(1): 2715, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976157

RESUMO

Efficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing.


Assuntos
Envelhecimento/genética , Divisão Celular Assimétrica/genética , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/genética , Serina-Treonina Quinases TOR/genética , Envelhecimento/imunologia , Animais , Divisão Celular Assimétrica/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ativação Linfocitária , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia
2.
Nat Commun ; 12(1): 2710, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976194

RESUMO

Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.


Assuntos
Artrite Juvenil/genética , Epigênese Genética , Receptores de Calcitriol/genética , Linfócitos T Reguladores/imunologia , Transcriptoma , Adolescente , Artrite Juvenil/imunologia , Artrite Juvenil/patologia , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Estudos de Casos e Controles , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Histonas/genética , Histonas/imunologia , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/imunologia , Cultura Primária de Células , Receptores de Calcitriol/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/patologia , Adulto Jovem
3.
Nat Commun ; 12(1): 2935, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006895

RESUMO

With emerging supremacy, cancer immunotherapy has evolved as a promising therapeutic modality compared to conventional antitumor therapies. Cancer immunotherapy composed of biodegradable poly(lactic-co-glycolic acid) (PLGA) particles containing antigens and toll-like receptor ligands induces vigorous antitumor immune responses in vivo. Here, we demonstrate the supreme adjuvant effect of the recently developed and pharmaceutically defined double-stranded (ds)RNA adjuvant Riboxxim especially when incorporated into PLGA particles. Encapsulation of Riboxxim together with antigens potently activates murine and human dendritic cells, and elevated tumor-specific CD8+ T cell responses are superior to those obtained using classical dsRNA analogues. This PLGA particle vaccine affords primary tumor growth retardation, prevention of metastases, and prolonged survival in preclinical tumor models. Its advantageous therapeutic potency was further enhanced by immune checkpoint blockade that resulted in reinvigoration of cytotoxic T lymphocyte responses and tumor ablation. Thus, combining immune checkpoint blockade with immunotherapy based on Riboxxim-bearing PLGA particles strongly increases its efficacy.


Assuntos
Vacinas Anticâncer/imunologia , Proteína DEAD-box 58/imunologia , Inibidores de Checkpoint Imunológico/imunologia , Imunoterapia/métodos , Neoplasias Experimentais/terapia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Receptores Imunológicos/imunologia , Receptor 3 Toll-Like/imunologia , Animais , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Células Cultivadas , Proteína DEAD-box 58/metabolismo , Sinergismo Farmacológico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Ligantes , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Nanopartículas/química , Nanopartículas/ultraestrutura , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Receptores Imunológicos/metabolismo , Células THP-1 , Receptor 3 Toll-Like/metabolismo , Resultado do Tratamento
4.
Front Immunol ; 12: 593595, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995342

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is a global health threat with the potential to cause severe disease manifestations in the lungs. Although COVID-19 has been extensively characterized clinically, the factors distinguishing SARS-CoV-2 from other respiratory viruses are unknown. Here, we compared the clinical, histopathological, and immunological characteristics of patients with COVID-19 and pandemic influenza A(H1N1). We observed a higher frequency of respiratory symptoms, increased tissue injury markers, and a histological pattern of alveolar pneumonia in pandemic influenza A(H1N1) patients. Conversely, dry cough, gastrointestinal symptoms and interstitial lung pathology were observed in COVID-19 cases. Pandemic influenza A(H1N1) was characterized by higher levels of IL-1RA, TNF-α, CCL3, G-CSF, APRIL, sTNF-R1, sTNF-R2, sCD30, and sCD163. Meanwhile, COVID-19 displayed an immune profile distinguished by increased Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-5, IL-10, IL-13) cytokine levels, along with IL-1ß, IL-6, CCL11, VEGF, TWEAK, TSLP, MMP-1, and MMP-3. Our data suggest that SARS-CoV-2 induces a dysbalanced polyfunctional inflammatory response that is different from the immune response against pandemic influenza A(H1N1). Furthermore, we demonstrated the diagnostic potential of some clinical and immune factors to differentiate both diseases. These findings might be relevant for the ongoing and future influenza seasons in the Northern Hemisphere, which are historically unique due to their convergence with the COVID-19 pandemic.


Assuntos
Citocinas , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Metaloproteinase 1 da Matriz , Metaloproteinase 3 da Matriz , Receptores Imunológicos , Adulto , Idoso , /epidemiologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/metabolismo , Influenza Humana/sangue , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Masculino , Metaloproteinase 1 da Matriz/sangue , Metaloproteinase 1 da Matriz/imunologia , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 3 da Matriz/imunologia , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores Imunológicos/sangue , Receptores Imunológicos/imunologia , Células Th1/imunologia , Células Th2/imunologia
5.
Fish Shellfish Immunol ; 113: 51-60, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33798718

RESUMO

Killer cell lectin-like receptor G subfamily 1 (KLRG1) is a receptor generally expressed on effector CD8+ T cells or NK cells at terminal differentiation stage, and it will be highly induced for lymphocyte cytotoxicity upon pathogen infection or lymphocyte activation. However, little is known about the character or function of KLRG1 in lower vertebrates. In present study, we reappraised a molecule that previously defined as KLRG1 in the genomic sequence of Nile tilapia Oreochromis niloticus, and identified it as an atypical KLRG1-like molecule (defined as On-KLRG1-L), and illustrated its potential function serving as a marker representing effector T lymphocytes of fish species. On-KLRG1-L consists of two C-type lectin-like domains (CTLDs) without transmembrane region, and the tertiary structure of the CTLD is highly alike to that in mouse KLRG1. As a CTLD-containing protein, the recombinant On-KLRG1-L could bind PGN and several microbes in vitro. On-KLRG1-L was widely expressed in immune-associated tissues, with the highest expression level in the gill. Once Nile tilapia is infected by Aeromonas hydrophila, mRNA level of On-KLRG1-L in spleen lymphocytes were significantly up-regulated on 5 days after infection. Meanwhile, On-KLRG1-L protein was also induced on 5 or 8 days after A. hydrophila infection. Furthermore, we found both mRNA and protein levels of On-KLRG1-L were dramatically enhanced within several hours after spleen lymphocytes were activated by T cell-specific mitogen PHA in vitro. More importantly, the ratio of On-KLRG1-L+ T cells was also augmented after PHA stimulation. The observations suggested that the KLRG1-like molecule from Nile tilapia participated in lymphocyte activation and anti-bacterial adaptive immune response, and could serve as an activation marker of T lymphocytes. Our study thus provided new evidences to understand lymphocyte-mediated adaptive immunity of teleost.


Assuntos
Imunidade Adaptativa/genética , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Lectinas Tipo C/imunologia , Ativação Linfocitária/imunologia , Receptores Imunológicos/imunologia , Aeromonas hydrophila/fisiologia , Sequência de Aminoácidos , Animais , Biomarcadores/metabolismo , Doenças dos Peixes/microbiologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/veterinária , Lectinas Tipo C/genética , Estrutura Terciária de Proteína , Receptores Imunológicos/genética , Alinhamento de Sequência/veterinária
6.
Nat Commun ; 12(1): 1534, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750787

RESUMO

Regulatory B cells (Bregs) contribute to immune regulation. However, the mechanisms of action of Bregs remain elusive. Here, we report that T cell immunoreceptor with Ig and ITIM domains (TIGIT) expressed on human memory B cells especially CD19+CD24hiCD27+CD39hiIgD-IgM+CD1c+ B cells is essential for effective immune regulation. Mechanistically, TIGIT on memory B cells controls immune response by directly acting on T cells and by arresting proinflammatory function of dendritic cells, resulting in the suppression of Th1, Th2, Th17, and CXCR5+ICOS+ T cell response while promoting immune regulatory function of T cells. TIGIT+ memory B cells are also superior to other B cells at expressing additional inhibitory molecules, including IL-10, TGFß1, granzyme B, PD-L1, CD39/CD73, and TIM-1. Lack or decrease of TIGIT+ memory B cells is associated with increased donor-specific antibody and TFH response, and decreased Treg response in renal and liver allograft patients. Therefore, TIGIT+ human memory B cells play critical roles in immune regulation.


Assuntos
Linfócitos B Reguladores/imunologia , Linfócitos B/imunologia , Receptores Imunológicos/imunologia , Antígenos CD/metabolismo , Antígenos CD1 , Antígenos CD19 , Apirase/metabolismo , Antígeno B7-H1 , Antígeno CD24/metabolismo , Glicoproteínas , Humanos , Imunoglobulina D , Imunoglobulina M , Proteína Coestimuladora de Linfócitos T Induzíveis , Interleucina-10 , Receptores CXCR5 , Receptores Imunológicos/genética , Células Th1 , Células Th17/imunologia , Células Th2 , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
7.
Life Sci ; 273: 119150, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662426

RESUMO

As a transmembrane protein, CD47 plays an important role in mediating cell proliferation, migration, phagocytosis, apoptosis, immune homeostasis, inhibition of NO signal transduction and other related reactions. Upon the interaction of innate immune checkpoint CD47-SIRPα occurrence, they send a "don't eat me" signal to the macrophages. This signal ultimately helps tumors achieve immune escape by inhibiting macrophage contraction to prevent tumor cells from phagocytosis. Therefore, the importance of CD47-SIRPα immune checkpoint inhibitors in tumor immunotherapy has attracted more attention in recent years. Based on the cognitive improvement of the effect with CD47 in tumor microenvironment and tumor characteristics, the pace of tumor treatment strategies for CD47-SIRPα immune checkpoint inhibitors has gradually accelerated. In this review, we introduced the high expression of CD47 in cancer cells to avoid phagocytosis by immune cells and the importance of CD47 in the structure of cancer microenvironment and the maintenance of cancer cell characteristics. Given the role of the innate immune system in tumorigenesis and development, an improved understanding of the anti-tumor process of innate immune checkpoint inhibitors can lay the foundation for more effective combinations with other anti-tumor treatment strategies.


Assuntos
Antígenos de Diferenciação/imunologia , Antígeno CD47/imunologia , Imunidade Inata/imunologia , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Receptores Imunológicos/imunologia , Animais , Humanos , Imunoterapia/métodos , Macrófagos , Neoplasias/imunologia , Fagocitose , Evasão Tumoral , Microambiente Tumoral
8.
Virus Res ; 299: 198347, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-33631219

RESUMO

BACKGROUND: There is a marked discrepancy between SARS-CoV-2 seroprevalence and COVID-19 cases and deaths in Africa. MAIN: SARS-CoV-2 stimulates humoral and cellular immunity systems, as well as mitogen-activated protein kinase (MAPK) and nuclear NF-kB signalling pathways, which regulate inflammatory gene expression and immune cell differentiation. The result is pro-inflammatory cytokines release, hyperinflammatory condition, and cytokine storm, which provoke severe lung alterations that can lead to multi-organ failure in COVID-19. Multiple genetic and immunologic factors may contribute to the severity of COVID-19 in African individuals when compared to the rest of the global population. In this article, the role of malaria, NF-kB and MAPK pathways, caspase-12 expression, high level of LAIR-1-containing antibodies, and differential glycophorins (GYPA/B) expression in COVID-19 are discussed. CONCLUSION: Understanding pathophysiological mechanisms can help identify target points for drugs and vaccines development against COVID-19. To our knowledge, this is the first study that explores this link and proposes a biological and molecular answer to the epidemiologic discrepancy in COVID-19 in Africa.


Assuntos
/genética , Malária/genética , Malária/imunologia , África/epidemiologia , /etnologia , Caspase 12/genética , Caspase 12/imunologia , Glicoforinas/genética , Glicoforinas/imunologia , Humanos , Malária/epidemiologia , Malária/etnologia , NF-kappa B/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Transdução de Sinais/imunologia
9.
Int Immunopharmacol ; 93: 107373, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33548578

RESUMO

The CD300 molecule family is a type I transmembrane glycoprotein expressed on cell membrane of human and other mammals, and of its eight members, only CD300a and CD300f are classified as inhibitory receptors. CD300a and CD300f play an important role in regulating the function of leukocytes, such as activation, proliferation, differentiation, migration and immunity function. They are considered as potential targets for studying the development and progression of inflammation, infection and other diseases. Here, we review the expression and regulatory mechanisms of CD300a and CD300f on leukocytes, as well as their effects on relevant diseases.


Assuntos
Antígenos CD/imunologia , Leucócitos/imunologia , Receptores Imunológicos/imunologia , Animais , Humanos , Inflamação/imunologia
10.
Cell Mol Immunol ; 18(3): 539-555, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33462384

RESUMO

Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are RNA sensor molecules that play essential roles in innate antiviral immunity. Among the three RLRs encoded by the human genome, RIG-I and melanoma differentiation-associated gene 5, which contain N-terminal caspase recruitment domains, are activated upon the detection of viral RNAs in the cytoplasm of virus-infected cells. Activated RLRs induce downstream signaling via their interactions with mitochondrial antiviral signaling proteins and activate the production of type I and III interferons and inflammatory cytokines. Recent studies have shown that RLR-mediated signaling is regulated by interactions with endogenous RNAs and host proteins, such as those involved in stress responses and posttranslational modifications. Since RLR-mediated cytokine production is also involved in the regulation of acquired immunity, the deregulation of RLR-mediated signaling is associated with autoimmune and autoinflammatory disorders. Moreover, RLR-mediated signaling might be involved in the aberrant cytokine production observed in coronavirus disease 2019. Since the discovery of RLRs in 2004, significant progress has been made in understanding the mechanisms underlying the activation and regulation of RLR-mediated signaling pathways. Here, we review the recent advances in the understanding of regulated RNA recognition and signal activation by RLRs, focusing on the interactions between various host and viral factors.


Assuntos
Proteína DEAD-box 58/imunologia , Mitocôndrias/imunologia , Receptores Imunológicos/imunologia , Transdução de Sinais , Viroses/imunologia , Vírus/imunologia , Animais , Humanos , Fatores Imunológicos , Interferon Tipo I/imunologia , Interferons/imunologia
11.
Biochim Biophys Acta Gen Subj ; 1865(3): 129839, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33412226

RESUMO

Mitochondria are multi-functioning organelles that participate in a wide range of biologic processes from energy metabolism to cellular suicide. Mitochondria are also involved in the cellular innate immune response against microorganisms or environmental irritants, particularly in mammals. Mitochondrial-mediated innate immunity is achieved by the activation of two discrete signaling pathways, the NLR family pyrin domain-containing 3 inflammasomes and the retinoic acid-inducible gene I-like receptor pathway. In both pathways, a mitochondrial outer membrane adaptor protein, called mitochondrial antiviral signaling MAVS, and mitochondria-derived components play a key role in signal transduction. In this review, we discuss current insights regarding the fundamental phenomena of mitochondrial-related innate immune responses, and review the specific roles of various mitochondrial subcompartments in fine-tuning innate immune signaling events. We propose that specific targeting of mitochondrial functions is a potential therapeutic approach for the management of infectious diseases and autoinflammatory disorders with an excessive immune response.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Inflamassomos , MicroRNAs/genética , MicroRNAs/imunologia , Mitocôndrias/genética , Mitocôndrias/virologia , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/patologia , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Vírus de RNA/patogenicidade , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Transdução de Sinais
12.
Biochem Biophys Res Commun ; 534: 134-140, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33341068

RESUMO

TIGIT is an emerging novel checkpoint target that is expressed on both tumor-infiltrating T cells and NK cells. Some current investigational antibodies targeting TIGIT have also achieved dramatic antitumor efficacy in late clinical research. Most recently, the relevance of NK cell-associated TIGIT signaling pathway to tumors' evasion of the immune system has been clearly revealed, which endows NK cells with a pivotal role in the therapeutic effects of TIGIT blockade. In this article, we describe a novel anti-TIGIT monoclonal antibody, AET2010, which was acquired from a phage-displayed human single-chain antibody library through a cell panning strategy. With emphasis on its regulation of NK cells, we confirmed the excellent ex vivo and in vivo antitumor immunity of AET2010 mediated by the NK-92MI cells. Intriguingly, our work also revealed that AET2010 displays a lower affinity but parallel avidity and activity relative to MK7684, an investigational monoclonal antibody from MSD, implying a reasonable balance of potency and potential side effects for AET2010. Together, these results are promising and warrant further development of AET2010.


Assuntos
Anticorpos Monoclonais/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Receptores Imunológicos/imunologia , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Cricetulus , Citotoxicidade Imunológica , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/terapia , Biblioteca de Peptídeos , Receptores Imunológicos/química , Receptores Virais/metabolismo
13.
Int J Mol Sci ; 22(1)2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33375121

RESUMO

Regulatory T cells (Tregs) prevent excessive immune responses and limit immune pathology upon infections. To fulfill this role in different immune environments elicited by different types of pathogens, Tregs undergo functional specialization into distinct subsets. During acute type 1 immune responses, type 1 Tregs are induced and recruited to the site of ongoing Th1 responses to efficiently control Th1 responses. However, whether a similar specialization process also takes place following chronic infections is still unknown. In this study, we investigated Treg specialization in persistent viral infections using lymphocytic choriomeningitis virus (LCMV) and murine cytomegalovirus (MCMV) infection as models for chronic and latent infections, respectively. We identify CD85k as a Th1-specific co-inhibitory receptor with sustained expression in persistent viral infections and show that recombinant CD85k inhibits LCMV-specific effector T cells. Furthermore, expression of the CD85k ligand ALCAM is induced on LCMV-specific and exhausted T cells during chronic LCMV infection. Finally, we demonstrate that type 1 Tregs arising during chronic LCMV infection suppress Th1 effector cells in an ALCAM-dependent manner. These results extend the current knowledge of Treg specialization from acute to persistent viral infections and reveal an important functional role of CD85k in Treg-mediated suppression of type 1 immunity.


Assuntos
Vírus da Coriomeningite Linfocítica/imunologia , Glicoproteínas de Membrana/imunologia , Muromegalovirus/imunologia , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD/imunologia , Antígenos CD/metabolismo , Moléculas de Adesão Celular Neuronais/imunologia , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular , Células Cultivadas , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/metabolismo , Infecções por Herpesviridae/virologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Muromegalovirus/fisiologia , Receptores Imunológicos/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/virologia , Células Th1/imunologia , Células Th1/metabolismo
14.
Aging (Albany NY) ; 13(2): 1929-1946, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33323544

RESUMO

BACKGROUND: Muscle-invasive bladder cancer (MIBC) patients are subject to unfavorable treatment options and a high recurrence rate. The status of TP53 mutations played an essential role in the progression and the prognosis of MIBC. The present study proposed to investigate the association between TP53 mutations and immunophenotype in MIBC. RESULTS: We established an immune prognostic model (IPM) ground on the immune-associated genes derived from variation analysis between wild-type TP53 and mutated TP53 TCGA-MIBC patients, and validated in another cohort from GEO database. Based on IPM, we divided MIBC patients into low and high risk subgroups. The high risk MIBC patients had higher proportions of macrophages M1, and lower proportions of T cells regulatory (Tregs) and activated dendritic cells than the low risk MIBC patients. Moreover, the expression of immune checkpoints genes (PD1, CTLA4, LAG3, HAVCR2 and TIGIT) was higher in the high risk patients than the low risk patients. In clinical application, IPM exhibited better survival prediction than conventional clinical characteristics. CONCLUSIONS: Our investigation presented practical prognostic significance for MIBC patients and displayed the overarching landscape of the immune response in the MIBC microenvironment. METHODS: Data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) analysis between the TP53 mutated and wild-type MIBC patients was conducted. The CIBERSORT algorithm was performed to evaluate the proportion of immune cell types. Gene expression profiles from the TCGA and GEO were used as training and testing cohorts to build and validate an immune-related prognostic model (IPM). Genes in the IPM model were first screened by univariate Cox analysis, then filtered by the least absolute shrinkage and selection operator (LASSO) Cox regression. A nomogram was finally established and evaluated by combining both the IPM and other clinical factors.


Assuntos
Carcinoma de Células de Transição/genética , Músculo Liso/patologia , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Antígenos CD/genética , Antígenos CD/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células de Transição/imunologia , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Bases de Dados Genéticas , Células Dendríticas/imunologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Estimativa de Kaplan-Meier , Macrófagos/imunologia , Mutação , Invasividade Neoplásica , Nomogramas , Prognóstico , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Modelos de Riscos Proporcionais , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Reprodutibilidade dos Testes , Taxa de Sobrevida , Linfócitos T Reguladores/imunologia , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
16.
Nat Immunol ; 21(9): 1107-1118, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32788748

RESUMO

In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Pneumonia Viral/imunologia , Receptores Imunológicos/metabolismo , Adolescente , Adulto , Idoso , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Coortes , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , RNA-Seq , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Índice de Gravidade de Doença , Análise de Célula Única
17.
Antiviral Res ; 182: 104868, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32659292

RESUMO

COVID-19, which is caused by the emerging human coronavirus SARS-CoV-2, has become a global pandemic that poses a serious threat to human health. To date, no vaccines or specific antiviral drugs have been approved for the treatment of this disease in clinic. Herein, therapeutic antibodies for SARS-CoV-2 were obtained from hyperimmune equine plasma. First, a recombinant SARS-CoV-2 spike protein receptor-binding domain (RBD) was obtained in gram-level quantities through high-cell density fermentation of Chinese hamster ovary cells. Then, the binding of the RBD to the SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, was verified by several biochemical methods. The efficacy of the RBD in triggering antibody response in vivo was subsequently tested in both mice and equines, and the results showed that the RBD triggered high-titer neutralizing antibody production in vivo. Immunoglobulin F(ab')2 fragments were prepared from equine antisera via removal of the Fc region from the immunoglobulins. Finally, a neutralization test with live virus demonstrated that RBD-specific F(ab')2 inhibited SARS-CoV-2 with an EC50 of 0.07 µg/ml and an EC80 of 0.18 µg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlight RBD-specific equine immunoglobulin F(ab')2 fragment as a candidate for the treatment of SARS-CoV-2.


Assuntos
Anticorpos Neutralizantes/imunologia , Betacoronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Receptores Imunológicos/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Antivirais/imunologia , Chlorocebus aethiops , Feminino , Células HeLa , Humanos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Pandemias , Ligação Proteica , Células Vero
18.
Nat Commun ; 11(1): 3763, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724132

RESUMO

In both animals and plants, the perception of bacterial flagella by immune receptors elicits the activation of defence responses. Most plants are able to perceive the highly conserved epitope flg22 from flagellin, the main flagellar protein, from most bacterial species. However, flagellin from Ralstonia solanacearum, the causal agent of the bacterial wilt disease, presents a polymorphic flg22 sequence (flg22Rso) that avoids perception by all plants studied to date. In this work, we show that soybean has developed polymorphic versions of the flg22 receptors that are able to perceive flg22Rso. Furthermore, we identify key residues responsible for both the evasion of perception by flg22Rso in Arabidopsis and the gain of perception by the soybean receptors. Heterologous expression of the soybean flg22 receptors in susceptible plant species, such as tomato, enhances resistance to bacterial wilt disease, demonstrating the potential of these receptors to enhance disease resistance in crop plants.


Assuntos
Flagelina/imunologia , Imunidade Vegetal , Proteínas de Plantas/imunologia , Receptores Imunológicos/imunologia , Soja/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Arabidopsis/genética , Arabidopsis/imunologia , Arabidopsis/metabolismo , Resistência à Doença/genética , Resistência à Doença/imunologia , Epitopos/imunologia , Flagelina/genética , Flagelina/metabolismo , Evasão da Resposta Imune/genética , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas , Polimorfismo Genético/imunologia , Ralstonia solanacearum/imunologia , Ralstonia solanacearum/patogenicidade , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Soja/genética , Soja/metabolismo , Soja/microbiologia
19.
Mol Immunol ; 125: 83-94, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32652363

RESUMO

Leukocyte immune-type receptors (LITRs) are a multigene family of teleost immunoregulatory proteins that share structural, phylogenetic, and likely functional relationships with several innate immune receptor proteins in other vertebrates, including mammals. Originally discovered in channel catfish (Ictalurus punctatus), representative IpLITR-types have been shown to regulate diverse innate immune cell effector responses including phagocytosis, degranulation, and cytokine secretion. To date, IpLITRs have been primarily characterized using mammalian cell line expression systems, therefore many unanswered questions remain regarding their actual regulatory roles in fish immunity. In the present study, we report on the preliminary molecular characterization of five goldfish (Carassius auratus) CaLITR-types and the identification of several putative splice variants of these receptors cloned from various goldfish tissues and primary myeloid cell cultures. In general, CaLITR mRNA transcripts were detected in all goldfish tissues tested, and also in primary kidney macrophage and neutrophil cultures. Specifically, CaLITR1 is a functionally ambiguous receptor with no charged amino acids in its transmembrane (TM) segment and is devoid of tyrosine-based signaling motifs in its short cytoplasmic tail (CYT) region. CaLITR2 is a putative activating receptor-type that contains immunotyrosine-based activation motifs (ITAMs) within its long CYT region, and CaLITR3 has a positively charged TM segment, suggesting that it may recruit intracellular stimulatory adaptor signaling molecules. CaLITR4 and CaLITR5 appear to have diverse signaling capabilities since they contain various immunoregulatory signaling motifs within their CYT regions including putative Nck and STAT recruitment motifs as well as ITAM-like and ITIM sequences. We also identified putative CaLITR splice variants with altered extracellular Ig-like domain compositions and variable CYT regions. Interestingly, this suggests that alternative splicing-mediated diversification of CaLITRs can generate receptor forms with possible variable binding and/or intracellular signaling abilities. Overall, these findings reveal new information about the teleost LITRs and sets the stage for exploring how alternative splicing leads to the functional diversification of this complex multigene immunoregulatory receptor family.


Assuntos
Carpa Dourada/imunologia , Imunidade Inata/imunologia , Leucócitos/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Processamento Alternativo , Animais , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Carpa Dourada/genética , Imunidade Inata/genética
20.
Nat Med ; 26(8): 1295-1306, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601335

RESUMO

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKposTREM2high and MerTKposLYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA.


Assuntos
Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Macrófagos/imunologia , Líquido Sinovial/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Biópsia , Linhagem da Célula/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Macrófagos/metabolismo , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Líquido Sinovial/imunologia , Membrana Sinovial
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