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1.
Nat Immunol ; 23(12): 1735-1748, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36456734

RESUMO

The non-pathogenic TH17 subset of helper T cells clears fungal infections, whereas pathogenic TH17 cells cause inflammation and tissue damage; however, the mechanisms controlling these distinct responses remain unclear. Here we found that fungi sensing by the C-type lectin dectin-1 in human dendritic cells (DCs) directed the polarization of non-pathogenic TH17 cells. Dectin-1 signaling triggered transient and intermediate expression of interferon (IFN)-ß in DCs, which was mediated by the opposed activities of transcription factors IRF1 and IRF5. IFN-ß-induced signaling led to integrin αvß8 expression directly and to the release of the active form of the cytokine transforming growth factor (TGF)-ß indirectly. Uncontrolled IFN-ß responses as a result of IRF1 deficiency induced high expression of the IFN-stimulated gene BST2 in DCs and restrained TGF-ß activation. Active TGF-ß was required for polarization of non-pathogenic TH17 cells, whereas pathogenic TH17 cells developed in the absence of active TGF-ß. Thus, dectin-1-mediated modulation of type I IFN responses allowed TGF-ß activation and non-pathogenic TH17 cell development during fungal infections in humans.


Assuntos
Células Dendríticas , Interferon Tipo I , Micoses , Humanos , Citocinas/metabolismo , Células Dendríticas/metabolismo , Interferon Tipo I/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Micoses/imunologia
2.
Nat Immunol ; 18(2): 225-235, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28024153

RESUMO

The mechanisms by which human immunodeficiency virus 1 (HIV-1) avoids immune surveillance by dendritic cells (DCs), and thereby prevents protective adaptive immune responses, remain poorly understood. Here we showed that HIV-1 actively arrested antiviral immune responses by DCs, which contributed to efficient HIV-1 replication in infected individuals. We identified the RNA helicase DDX3 as an HIV-1 sensor that bound abortive HIV-1 RNA after HIV-1 infection and induced DC maturation and type I interferon responses via the signaling adaptor MAVS. Notably, HIV-1 recognition by the C-type lectin receptor DC-SIGN activated the mitotic kinase PLK1, which suppressed signaling downstream of MAVS, thereby interfering with intrinsic host defense during HIV-1 infection. Finally, we showed that PLK1-mediated suppression of DDX3-MAVS signaling was a viral strategy that accelerated HIV-1 replication in infected individuals.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Dendríticas/virologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Evasão da Resposta Imune , Imunidade , Macrófagos/virologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Extratos Celulares , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Estudos de Coortes , RNA Helicases DEAD-box/metabolismo , Células Dendríticas/imunologia , Regulação Viral da Expressão Gênica , Células HEK293 , Infecções por HIV/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon beta/sangue , Macrófagos/imunologia , Polimorfismo de Nucleotídeo Único , RNA Viral/imunologia , RNA Viral/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais , Carga Viral/genética
3.
Immunity ; 50(2): 462-476.e8, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30770246

RESUMO

Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4+ Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4+ T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Feto/imunologia , Memória Imunológica/imunologia , Intestinos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Células Epiteliais/citologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Feminino , Feto/metabolismo , Humanos , Recém-Nascido , Mucosa Intestinal/embriologia , Mucosa Intestinal/crescimento & desenvolvimento , Mucosa Intestinal/imunologia , Intestinos/embriologia , Intestinos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL , Gravidez , Células-Tronco/citologia , Células-Tronco/imunologia , Células-Tronco/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
EMBO J ; 40(20): e106765, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34510494

RESUMO

The current pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and outbreaks of new variants highlight the need for preventive treatments. Here, we identified heparan sulfate proteoglycans as attachment receptors for SARS-CoV-2. Notably, neutralizing antibodies against SARS-CoV-2 isolated from COVID-19 patients interfered with SARS-CoV-2 binding to heparan sulfate proteoglycans, which might be an additional mechanism of antibodies to neutralize infection. SARS-CoV-2 binding to and infection of epithelial cells was blocked by low molecular weight heparins (LMWH). Although dendritic cells (DCs) and mucosal Langerhans cells (LCs) were not infected by SARS-CoV-2, both DC subsets efficiently captured SARS-CoV-2 via heparan sulfate proteoglycans and transmitted the virus to ACE2-positive cells. Notably, human primary nasal cells were infected by SARS-CoV-2, and infection was blocked by pre-treatment with LMWH. These data strongly suggest that heparan sulfate proteoglycans are important attachment receptors facilitating infection and transmission, and support the use of LMWH as prophylaxis against SARS-CoV-2 infection.


Assuntos
COVID-19/transmissão , Proteoglicanas de Heparan Sulfato/metabolismo , Heparina de Baixo Peso Molecular/farmacologia , SARS-CoV-2/patogenicidade , Enzima de Conversão de Angiotensina 2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Neutralizantes/metabolismo , Anticorpos Neutralizantes/farmacologia , Chlorocebus aethiops , Células Dendríticas/metabolismo , Células Dendríticas/virologia , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Interações Hospedeiro-Patógeno , Humanos , Mucosa/citologia , Mucosa/virologia , SARS-CoV-2/metabolismo , Sindecana-1/metabolismo , Sindecana-4/metabolismo , Células Vero , Tratamento Farmacológico da COVID-19
5.
Eur J Immunol ; 54(5): e2350839, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38430190

RESUMO

The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.


Assuntos
Família Aldeído Desidrogenase 1 , Antígenos CD , Diferenciação Celular , Células Dendríticas , Cadeias alfa de Integrinas , Lipossomos , Retinal Desidrogenase , Linfócitos T Reguladores , Células Th17 , Tretinoína , Humanos , Tretinoína/farmacologia , Cadeias alfa de Integrinas/metabolismo , Células Th17/imunologia , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Antígenos CD/imunologia , Antígenos CD/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Retinal Desidrogenase/metabolismo , Tolerância Imunológica/efeitos dos fármacos , Células Cultivadas , Interleucina-10/metabolismo , Interleucina-10/imunologia , Fatores de Transcrição Forkhead/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Doença Celíaca/imunologia
6.
PLoS Pathog ; 19(10): e1011735, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37844099

RESUMO

SARS-CoV-2 causes COVID-19, an infectious disease with symptoms ranging from a mild cold to severe pneumonia, inflammation, and even death. Although strong inflammatory responses are a major factor in causing morbidity and mortality, superinfections with bacteria during severe COVID-19 often cause pneumonia, bacteremia and sepsis. Aberrant immune responses might underlie increased sensitivity to bacteria during COVID-19 but the mechanisms remain unclear. Here we investigated whether SARS-CoV-2 directly suppresses immune responses to bacteria. We studied the functionality of human dendritic cells (DCs) towards a variety of bacterial triggers after exposure to SARS-CoV-2 Spike (S) protein and SARS-CoV-2 primary isolate (hCoV-19/Italy). Notably, pre-exposure of DCs to either SARS-CoV-2 S protein or a SARS-CoV-2 isolate led to reduced type I interferon (IFN) and cytokine responses in response to Toll-like receptor (TLR)4 agonist lipopolysaccharide (LPS), whereas other TLR agonists were not affected. SARS-CoV-2 S protein interacted with the C-type lectin receptor DC-SIGN and, notably, blocking DC-SIGN with antibodies restored type I IFN and cytokine responses to LPS. Moreover, blocking the kinase Raf-1 by a small molecule inhibitor restored immune responses to LPS. These results suggest that SARS-CoV-2 modulates DC function upon TLR4 triggering via DC-SIGN-induced Raf-1 pathway. These data imply that SARS-CoV-2 actively suppresses DC function via DC-SIGN, which might account for the higher mortality rates observed in patients with COVID-19 and bacterial superinfections.


Assuntos
COVID-19 , Superinfecção , Humanos , SARS-CoV-2/metabolismo , Receptor 4 Toll-Like/metabolismo , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , COVID-19/metabolismo , Lectinas Tipo C/metabolismo , Citocinas/metabolismo , Células Dendríticas
7.
J Infect Dis ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38573164

RESUMO

Dysbiosis of the vaginal microbiome poses a serious risk for sexual HIV-1 transmission. Prevotella spp. are abundant during vaginal dysbiosis and associated with enhanced HIV-1 susceptibility; however, underlying mechanisms remain unclear. Here, we investigated the direct effect of vaginal bacteria on HIV-1 susceptibility of vaginal CD4+ T cells. Notably, pre-exposure to Prevotella timonensis enhanced HIV-1 uptake by vaginal T cells, leading to increased viral fusion and enhanced virus production. Pre-exposure to antiretroviral inhibitors abolished Prevotella timonensis-enhanced infection. Hence, our study shows that the vaginal microbiome directly affects mucosal CD4+ T cell susceptibility, emphasising importance of vaginal dysbiosis diagnosis and treatment.

8.
Nat Immunol ; 13(3): 246-54, 2012 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-22267217

RESUMO

Production of the proinflammatory cytokine interleukin 1ß (IL-1ß) by dendritic cells is crucial in host defense. Here we identify a previously unknown role for dectin-1 in the activation of a noncanonical caspase-8 inflammasome in response to fungi and mycobacteria. Dectin-1 induced both the production and maturation of IL-1ß through signaling routes mediated by the kinase Syk. Whereas the CARD9-Bcl-10-MALT1 scaffold directed IL1B transcription, the recruitment of MALT1-caspase-8 and ASC into this scaffold was crucial for processing of pro-IL-1ß by caspase-8. In contrast to activation of the canonical caspase-1 inflammasome, which requires additional activation of cytosolic receptors, activation of the noncanonical caspase-8 inflammasome was independent of pathogen internalization. Thus, dectin-1 acted as an extracellular sensor for pathogens that induced both IL-1ß production and maturation through a noncanonical caspase-8-dependent inflammasome for protective immunity.


Assuntos
Caspase 8/imunologia , Inflamassomos/imunologia , Interleucina-1beta/imunologia , Lectinas Tipo C/imunologia , Candida albicans/imunologia , Ativação Enzimática , Espaço Extracelular/imunologia , Humanos , Lectinas Tipo C/metabolismo , Mycobacterium/imunologia , Transdução de Sinais
10.
Eur J Immunol ; 52(4): 646-655, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35099061

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.


Assuntos
COVID-19 , Células Dendríticas , Glicoproteína da Espícula de Coronavírus , Receptor 4 Toll-Like , COVID-19/imunologia , Linhagem Celular , Células Dendríticas/imunologia , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia , Receptor 4 Toll-Like/imunologia
11.
Blood ; 138(17): 1570-1582, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34424958

RESUMO

Glycosylation of the surface immunoglobulin (Ig) variable region is a remarkable follicular lymphoma-associated feature rarely seen in normal B cells. Here, we define a subset of diffuse large B-cell lymphomas (DLBCLs) that acquire N-glycosylation sites selectively in the Ig complementarity-determining regions (CDRs) of the antigen-binding sites. Mass spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures because they are buried in the CDR loops. Acquisition of sites occurs in ∼50% of germinal-center B-cell-like DLBCL (GCB-DLBCL), mainly of the genetic EZB subtype, irrespective of IGHV-D-J use. This markedly contrasts with the activated B-cell-like DLBCL Ig, which rarely has sites in the CDR and does not seem to acquire oligomannose-type structures. Acquisition of CDR-located acceptor sites associates with mutations of epigenetic regulators and BCL2 translocations, indicating an origin shared with follicular lymphoma. Within the EZB subtype, these sites are associated with more rapid disease progression and with significant gene set enrichment of the B-cell receptor, PI3K/AKT/MTORC1 pathway, glucose metabolism, and MYC signaling pathways, particularly in the fraction devoid of MYC translocations. The oligomannose-type glycans on the lymphoma cells interact with the candidate lectin dendritic cell-specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN), mediating low-level signals, and lectin-expressing cells form clusters with lymphoma cells. Both clustering and signaling are inhibited by antibodies specifically targeting the DC-SIGN carbohydrate recognition domain. Oligomannosylation of the tumor Ig is a posttranslational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and it could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN-expressing M2-polarized macrophages.


Assuntos
Regiões Determinantes de Complementaridade/química , Linfoma Difuso de Grandes Células B/patologia , Polissacarídeos/análise , Sítios de Ligação , Moléculas de Adesão Celular/química , Glicosilação , Humanos , Lectinas Tipo C/química , Linfoma Difuso de Grandes Células B/química , Domínios e Motivos de Interação entre Proteínas , Receptores de Superfície Celular/química , Células Tumorais Cultivadas
12.
Eur J Immunol ; 51(10): 2464-2477, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34223639

RESUMO

The proinflammatory cytokine IL-1ß mediates high levels of immune activation observed during acute and chronic human immunodeficiency virus 1 (HIV-1) infection. Little is known about the mechanisms that drive IL-1ß activation during HIV-1 infection. Here, we have identified a crucial role for abortive HIV-1 RNAs in inducing IL-1ß in humans. Abortive HIV-1 RNAs were sensed by protein kinase RNA-activated (PKR), which triggered activation of the canonical NLRP3 inflammasome and caspase-1, leading to pro-IL-1ß processing and secretion. PKR activated the inflammasome via ROS generation and MAP kinases ERK1/2, JNK, and p38. Inhibition of PKR during HIV-1 infection blocked IL-1ß production. As abortive HIV-1 RNAs are produced during productive infection and latency, our data strongly suggest that targeting PKR signaling might attenuate immune activation during acute and chronic HIV-1 infection.


Assuntos
Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , RNA Viral/metabolismo , eIF-2 Quinase/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Sistema de Sinalização das MAP Quinases , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , RNA Viral/genética , Espécies Reativas de Oxigênio/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Transdução de Sinais
13.
PLoS Pathog ; 16(10): e1008253, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33031460

RESUMO

Measles is characterized by fever and a maculopapular skin rash, which is accompanied by immune clearance of measles virus (MV)-infected cells. Histopathological analyses of skin biopsies from humans and non-human primates (NHPs) with measles rash have identified MV-infected keratinocytes and mononuclear cells in the epidermis, around hair follicles and near sebaceous glands. Here, we address the pathogenesis of measles skin rash by combining data from experimentally infected NHPs, ex vivo infection of human skin sheets and in vitro infection of primary human keratinocytes. Analysis of NHP skin samples collected at different time points following MV inoculation demonstrated that infection in the skin precedes onset of rash by several days. MV infection was detected in lymphoid and myeloid cells in the dermis before dissemination to the epidermal leukocytes and keratinocytes. These data were in good concordance with ex vivo MV infections of human skin sheets, in which dermal cells were more targeted than the epidermal cells. To address viral dissemination to the epidermis and to determine whether the dissemination is receptor-dependent, we performed experimental infections of primary keratinocytes collected from healthy donors. These experiments demonstrated that MV infection of keratinocytes is mainly nectin-4-dependent, and differentiated keratinocytes, which express higher levels of nectin-4, are more susceptible to MV infection than proliferating keratinocytes. Based on these data, we propose a model to explain measles skin rash: migrating MV-infected lymphocytes initiate the infection of dermal skin-resident CD150+ immune cells. The infection is subsequently disseminated from the dermal papillae to nectin-4+ keratinocytes in the basal epidermis. Lateral spread of MV infection is observed in the superficial epidermis, most likely due to the higher level of nectin-4 expression on differentiated keratinocytes. Finally, MV-infected cells are cleared by infiltrating immune cells, causing hyperemia and edema, which give the appearance of morbilliform skin rash.


Assuntos
Derme/virologia , Epiderme/virologia , Queratinócitos/virologia , Linfócitos/virologia , Sarampo/virologia , Células Mieloides/virologia , Pele/virologia , Animais , Células Cultivadas , Derme/patologia , Epiderme/patologia , Humanos , Queratinócitos/patologia , Linfócitos/patologia , Macaca fascicularis , Sarampo/patologia , Vírus do Sarampo/isolamento & purificação , Células Mieloides/patologia , Pele/patologia
14.
Nat Immunol ; 11(5): 419-26, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20364151

RESUMO

Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-kappaB through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII). However, DC-SIGN signaling was required for the generation of full-length viral transcripts. Binding of the HIV-1 envelope glycoprotein gp120 to DC-SIGN induced kinase Raf-1-dependent phosphorylation of the NF-kappaB subunit p65 at Ser276, which recruited the transcription-elongation factor pTEF-b to nascent transcripts. Transcription elongation and generation of full-length viral transcripts was dependent on pTEF-b-mediated phosphorylation of RNAPII at Ser2. Inhibition of either pathway abrogated replication and prevented HIV-1 transmission. Thus, HIV-1 subverts crucial components of the immune system for replication that might be targeted to prevent infection and dissemination.


Assuntos
Células Dendríticas/metabolismo , Infecções por HIV/imunologia , HIV-1/fisiologia , Imunidade Inata , Receptor 8 Toll-Like/metabolismo , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação , Fator B de Elongação Transcricional Positiva/metabolismo , Ligação Proteica/genética , Engenharia de Proteínas , Proteínas Proto-Oncogênicas c-raf/metabolismo , RNA Polimerase II/metabolismo , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Sistemas do Segundo Mensageiro/genética , Sistemas do Segundo Mensageiro/imunologia , Deleção de Sequência/genética , Receptor 8 Toll-Like/imunologia , Ativação Transcricional/genética , Ativação Transcricional/imunologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética , Replicação Viral/imunologia
15.
J Immunol ; 204(2): 386-393, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31818980

RESUMO

The spirochete Borrelia miyamotoi has recently been shown to cause relapsing fever. Like the Lyme disease agent, Borrelia burgdorferi, B. miyamotoi is transmitted through the bite of infected ticks; however, little is known about the response of the immune system upon infection. Dendritic cells (DCs) play a central role in the early immune response against B. burgdorferi We investigated the response of DCs to two different strains of B. miyamotoi using in vitro and ex vivo models and compared this to the response elicited by B. burgdorferi. Our findings show that B. miyamotoi is phagocytosed by monocyte-derived DCs, causing upregulation of activation markers and production of proinflammatory cytokines in a similar manner to B. burgdorferi. Recognition of B. miyamotoi was demonstrated to be partially mediated by TLR2. DCs migrated out of human skin explants upon inoculation of the skin with B. miyamotoi. Finally, we showed that B. miyamotoi-stimulated DCs induced proliferation of naive CD4+ and CD8+ T cells to a larger extent than B. burgdorferi. In conclusion, we show in this study that DCs respond to and mount an immune response against B. miyamotoi that is similar to the response to B. burgdorferi and is able to induce T cell proliferation.


Assuntos
Borrelia/fisiologia , Células Dendríticas/imunologia , Mordeduras e Picadas de Insetos/imunologia , Febre Recorrente/imunologia , Pele/patologia , Linfócitos T/imunologia , Carrapatos/imunologia , Animais , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Fagocitose , Carrapatos/microbiologia , Receptor 2 Toll-Like/metabolismo
16.
Nature ; 540(7633): 448-452, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27919079

RESUMO

The most prevalent route of HIV-1 infection is across mucosal tissues after sexual contact. Langerhans cells (LCs) belong to the subset of dendritic cells (DCs) that line the mucosal epithelia of vagina and foreskin and have the ability to sense and induce immunity to invading pathogens. Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection. Notably, LCs form a protective barrier against HIV-1 infection and transmission. LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules. However, the underlying molecular mechanism of HIV-1 restriction in LCs remains unknown. Here we show that human E3-ubiquitin ligase tri-partite-containing motif 5α (TRIM5α) potently restricts HIV-1 infection of LCs but not of subepithelial DC-SIGN+ DCs. HIV-1 restriction by TRIM5α was thus far considered to be reserved to non-human primate TRIM5α orthologues, but our data strongly suggest that human TRIM5α is a cell-specific restriction factor dependent on C-type lectin receptor function. Our findings highlight the importance of HIV-1 binding to Langerin for the routeing of HIV-1 into the human TRIM5α-mediated restriction pathway. TRIM5α mediates the assembly of an autophagy-activating scaffold to Langerin, which targets HIV-1 for autophagic degradation and prevents infection of LCs. By contrast, HIV-1 binding to DC-SIGN+ DCs leads to disassociation of TRIM5α from DC-SIGN, which abrogates TRIM5α restriction. Thus, our data strongly suggest that restriction by human TRIM5α is controlled by C-type-lectin-receptor-dependent uptake of HIV-1, dictating protection or infection of human DC subsets. Therapeutic interventions that incorporate C-type lectin receptors and autophagy-targeting strategies could thus provide cell-mediated resistance to HIV-1 in humans.


Assuntos
Antígenos CD/metabolismo , Autofagia , Proteínas de Transporte/metabolismo , HIV-1/fisiologia , Células de Langerhans/metabolismo , Células de Langerhans/virologia , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Receptores de HIV/metabolismo , Fatores de Restrição Antivirais , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , HIV-1/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade nas Mucosas , Células de Langerhans/citologia , Células de Langerhans/imunologia , Receptores de Superfície Celular/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
17.
Nat Immunol ; 10(10): 1081-8, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19718030

RESUMO

Cooperation between different innate signaling pathways induced by pattern-recognition receptors (PRRs) on dendritic cells (DCs) is crucial for tailoring adaptive immunity to pathogens. Here we show that carbohydrate-specific signaling through the C-type lectin DC-SIGN tailored cytokine production in response to distinct pathogens. DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. Mannose-expressing Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) induced the recruitment of effector proteins to the DC-SIGN signalosome to activate Raf-1, whereas fucose-expressing pathogens such as Helicobacter pylori actively dissociated the KSR1-CNK-Raf-1 complex from the DC-SIGN signalosome. This dynamic regulation of the signalosome by mannose- and fucose-expressing pathogens led to the enhancement or suppression of proinflammatory responses, respectively. Our study reveals another level of plasticity in tailoring adaptive immunity to pathogens.


Assuntos
Carboidratos/imunologia , Moléculas de Adesão Celular/imunologia , HIV-1/imunologia , Helicobacter pylori/imunologia , Lectinas Tipo C/imunologia , Mycobacterium tuberculosis/imunologia , Receptores de Superfície Celular/imunologia , Transdução de Sinais/imunologia , Western Blotting , Moléculas de Adesão Celular/metabolismo , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fucose/imunologia , Humanos , Lectinas Tipo C/metabolismo , Manose/imunologia , Proteínas dos Microfilamentos/imunologia , Proteínas dos Microfilamentos/metabolismo , Proteínas Quinases/imunologia , Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-raf/imunologia , Proteínas Proto-Oncogênicas c-raf/metabolismo , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
Nat Immunol ; 10(2): 203-13, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19122653

RESUMO

The C-type lectin dectin-1 activates the transcription factor NF-kappaB through a Syk kinase-dependent signaling pathway to induce antifungal immunity. Here we show that dectin-1 expressed on human dendritic cells activates not only the Syk-dependent canonical NF-kappaB subunits p65 and c-Rel, but also the noncanonical NF-kappaB subunit RelB. Dectin-1, when stimulated by the beta-glucan curdlan or by Candida albicans, induced a second signaling pathway mediated by the serine-threonine kinase Raf-1, which integrated with the Syk pathway at the point of NF-kappaB activation. Raf-1 antagonized Syk-induced RelB activation by promoting sequestration of RelB into inactive p65-RelB dimers, thereby altering T helper cell differentiation. Thus, dectin-1 activates two independent signaling pathways, one through Syk and one through Raf-1, to induce immune responses.


Assuntos
Diferenciação Celular/imunologia , Ativação Enzimática/imunologia , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Acetilação , Candida albicans/imunologia , Citocinas/biossíntese , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/imunologia , Humanos , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lectinas Tipo C , Proteínas de Membrana/imunologia , Micoses/imunologia , NF-kappa B/imunologia , Proteínas do Tecido Nervoso/imunologia , Fosforilação , Proteínas Tirosina Quinases/imunologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-raf/imunologia , Proteínas Proto-Oncogênicas c-raf/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Quinase Syk , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
19.
Immunity ; 36(4): 557-9, 2012 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-22520851

RESUMO

Cell death needs to be detected by immune cells. In this issue of Immunity, Ahrens et al. (2012) and Zhang et al. (2012) show that actin filaments become exposed on necrotic cells and act as ligands for the C-type lectin receptor Clec9a.

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