RESUMO
It is known that conventional antigen presentation involves phagocytosis of antigens followed by its internalization in endocytic compartments and presentation of epitopes through MHC class II molecules for CD4 T cells. However, since 1976 a cross-presentation pathway has been studied, in which CD8 T cells are activated via MHC class I with antigens acquired through phagocytosis or endocytosis by dendritic cells (DCs). Among some important molecules involved in the cross-presentation, the C-type lectin receptor of the Dectin-1 cluster (CLECs), particularly the CLEC9A receptor, not only is expressed in dendritic cells but also presents a pivotal role in this context. In special, CLEC12A has been highlighted as a malaria pigment hemozoin (HZ) receptor. During Plasmodium infection, hemozoin crystals defend the parasite against heme toxicity within erythrocytes, as well as the released native HZ elicits pro-inflammatory responses and can induce cross-presentation. Particularly, this crystal can be synthesized from hematin anhydride and mimics the native form, and the gaps generated between the nanocrystal domains during its synthesis allow for substance coupling followed by its coating. Therefore, this study aimed to assess whether synthetic hemozoin (sHz) or hematin anhydride could be a nanocarrier and promote cross-presentation in dendritic cells. Firstly, it was verified that sHz can carry coated and coupled antigens, the compounds can associate to LAMP1-positive vesicles and decrease overall intracellular pH, which can potentially enhance the cross-presentation of ovalbumin and Leishmania infantum antigens. Thus, this study adds important data in the molecular intricacies of antigen presentation by showing not only the sHz immunomodulatory properties but also its potential applications as an antigen carrier.
Assuntos
Apresentação de Antígeno , Apresentação Cruzada , Células Dendríticas , Hemeproteínas , Hemeproteínas/imunologia , Apresentação Cruzada/imunologia , Animais , Células Dendríticas/imunologia , Camundongos , Nanopartículas/química , Humanos , Malária/imunologia , Lectinas Tipo C/metabolismo , Lectinas Tipo C/imunologia , Ovalbumina/imunologiaRESUMO
Antigen-specific cytotoxic CD8 T cells are extremely effective in controlling tumor growth and have been the focus of immunotherapy approaches. We leverage in silico tools to investigate whether the occurrence of mutations in proteins previously described as immunogenic and highly expressed by glioblastoma multiforme (GBM), such as Epidermal Growth Factor Receptor (EGFR), Isocitrate Dehydrogenase 1 (IDH1), Phosphatase and Tensin homolog (PTEN) and Tumor Protein 53 (TP53), may be contributing to the differential presentation of immunogenic epitopes. We recovered Class I MHC binding information from wild-type and mutated proteins using the Immune Epitope Database (IEDB). After that, we built peptide-MHC (pMHC-I) models in HLA-arena, followed by hierarchical clustering analysis based on electrostatic surface features from each complex. We identified point mutations that are determinants for the presentation of a set of peptides from TP53 protein. We point to structural features in the pMHC-I complexes of wild-type and mutated peptides, which may play a role in the recognition of CD8 T cells. To further explore these features, we performed 100 ns molecular dynamics simulations for the peptide pairs (wt/mut) selected. In pursuit of novel therapeutic targets for GBM treatment, we selected peptides where our predictive results indicated that mutations would not disrupt epitope presentation, thereby maintaining a specific CD8 T cell immune response. These peptides hold potential for future GBM interventions, including peptide-based or mRNA vaccine development applications.
Assuntos
Apresentação de Antígeno , Linfócitos T CD8-Positivos , Glioblastoma , Isocitrato Desidrogenase , Proteína Supressora de Tumor p53 , Glioblastoma/imunologia , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Linfócitos T CD8-Positivos/imunologia , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/imunologia , Isocitrato Desidrogenase/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/imunologia , Apresentação de Antígeno/imunologia , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , PTEN Fosfo-Hidrolase/química , Receptores ErbB/imunologia , Receptores ErbB/genética , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapiaRESUMO
The P2X7 receptor, a member of the P2X purinergic receptor family, is a non-selective ion channel. Over the years, it has been associated with various biological functions, from modulating to regulating inflammation. However, its emerging role in antigen presentation has captured the scientific community's attention. This function is essential for the immune system to identify and respond to external threats, such as pathogens and tumor cells, through T lymphocytes. New studies show that the P2X7 receptor is crucial for controlling how antigens are presented and how T cells are activated. These studies focus on antigen-presenting cells, like dendritic cells and macrophages. This review examines how the P2X7 receptor interferes with effective antigen presentation and activates T cells and discusses the fundamental mechanisms that can affect the immune response. Understanding these P2X7-mediated processes in great detail opens up exciting opportunities to create new immunological therapies.
Assuntos
Apresentação de Antígeno , Receptores Purinérgicos P2X7 , Ativação Linfocitária , Macrófagos , Células DendríticasRESUMO
Dendritic cells (DCs) have a specialized endomembrane system capable of presenting exogenous antigens in the context of MHC class I (MHC-I) molecules. This process, named cross-presentation, is crucial to activate CD8+ T lymphocytes and initiate cytotoxic immune responses. In this report, we present an Agent-Based Model in combination with Ordinary Differential Equations with enough complexity to reproduce cross-presentation. The model embraces the secretory and endocytic pathways, in connection with the plasma membrane, the endoplasmic reticulum, and the cytosol. Key molecules required for cross-presentation were included as cargoes. In the simulations, the kinetics of MHC-I uptake and recycling, and cross-presentation accurately reproduced experimental values. The model proved to be a suitable tool to elaborate hypotheses and design experiments. In particular, the model predictions and the experimental results obtained indicate that the rate-limiting step in cross-presentation of soluble ovalbumin is MHC-I loading after proteasomal processing of the antigenic protein.
Assuntos
Apresentação de Antígeno , Apresentação Cruzada , Cinética , Ovalbumina , Linfócitos T CD8-PositivosRESUMO
HIV-1-specific CD4+ T cells (TCD4+s) play a critical role in controlling HIV-1 infection. Canonically, TCD4+s are activated by peptides derived from extracellular ("exogenous") Ags displayed in complex with MHC class II (MHC II) molecules on the surfaces of "professional" APCs such as dendritic cells (DCs). In contrast, activated human TCD4+s, which express MHC II, are not typically considered for their APC potential because of their low endocytic capacity and the exogenous Ag systems historically used for assessment. Using primary TCD4+s and monocyte-derived DCs from healthy donors, we show that activated human TCD4+s are highly effective at MHC II-restricted presentation of an immunodominant HIV-1-derived epitope postinfection and subsequent noncanonical processing and presentation of endogenously produced Ag. Our results indicate that, in addition to marshalling HIV-1-specific immune responses during infection, TCD4+s also act as APCs, leading to the activation of HIV-1-specific TCD4+s.
Assuntos
Soropositividade para HIV , HIV-1 , Apresentação de Antígeno , Linfócitos T CD4-Positivos , Células Dendríticas , Epitopos , Antígenos de Histocompatibilidade Classe II , Humanos , Peptídeos , Linfócitos TRESUMO
The extraordinary variation of the human leukocyte antigen (HLA) molecules is critical for diversifying antigen presentation to T cells. Coupled with the rise of novel strains and rapidly evolving immune evasion by SARS-CoV-2 proteins, HLA-mediated immunity in COVID-19 is critically important but far from being fully understood. A growing number of studies have found the association of HLA variants with different COVID-19 outcomes and that HLA genotypes associate with differential immune responses against SARS-CoV-2. Prediction studies have shown that mutations in multiple viral strains, most concentrated in the Spike protein, affect the affinity between these mutant peptides and HLA molecules. Understanding the impact of this variation on T-cell responses is critical for comprehending the immunogenic mechanisms in both natural immunity and vaccine development.
Assuntos
COVID-19 , Apresentação de Antígeno , Epitopos de Linfócito T , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II , Humanos , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/genéticaRESUMO
Human papillomavirus (HPV) is the major pathogen for cervical lesions. The evasion mechanism of the immune response and persistence of HPV infection can be influenced by polymorphisms (SNPs) in genes associated with transporter associated with antigen processing (TAP), which may change the peptide binding affinity or the TAP expression impacting the efficiency of peptide transport in the secretory pathway, and the presentation of peptides to cytotoxic T lymphocytes. This study aimed to evaluate the role of the TAP1 and TAP2 polymorphisms, TAP1, and TAP2 genes expressions, and protein levels in cervical cells presenting different degrees of pre-cancerous lesions in 296 immunocompetent women infected or not by HPV. TAP SNPs were genotyped by Sanger sequencing, and gene expression by real-time PCR. Aneuploidy was determined by DNA index using flow cytometry. TAP-1 and TAP-2 tissue expressions were evaluated by immunohistochemistry. The Asp697Gly SNP of TAP1 presented a risk for cellular aneuploidy (P=0.0244). HPV+ women had higher TAP-2 mRNA (P=0.0212) and protein (P<0.0001) levels. The TAP2D and TAP2E haplotypes were associated with the risk for aneuploidy and pre-cancerous lesions. In conclusion, nucleotide variability at the peptide binding region of peptide transporter genes, particularly of the TAP2 gene, may influence the HPV-peptide transportation from the cytosol to the endoplasmic reticulum, increasing the susceptibility to the development of high-grade cervical lesions.
Assuntos
Neoplasias , Infecções por Papillomavirus , Humanos , Feminino , Apresentação de Antígeno , Papillomavirus Humano , Infecções por Papillomavirus/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Proteínas de Membrana Transportadoras/genética , Polimorfismo de Nucleotídeo Único , Peptídeos/genéticaRESUMO
SAMHD1 is a potent HIV-1 restriction factor that blocks reverse transcription in monocytes, dendritic cells and resting CD4+ T cells by decreasing intracellular dNTP pools. However, SAMHD1 may diminish innate immune sensing and Ag presentation, resulting in a weaker adaptive immune response. To date, the role of SAMHD1 on antiretroviral immunity remains unclear, as mouse SAMHD1 had no impact on murine retrovirus replication in prior in vivo studies. Here, we show that SAMHD1 significantly inhibits acute Friend retrovirus infection in mice. Pretreatment with LPS, a significant driver of inflammation during HIV-1 infection, further unmasked a role for SAMHD1 in influencing immune responses. LPS treatment in vivo doubled the intracellular dNTP levels in immune compartments of SAMHD1 knockout but not wild-type mice. SAMHD1 knockout mice exhibited higher plasma infectious viremia and proviral DNA loads than wild-type mice at 7 d postinfection (dpi), and proviral loads inversely correlated with a stronger CD8+ T cell response. SAMHD1 deficiency was also associated with weaker NK, CD4+ T and CD8+ T cell responses by 14 dpi and weaker neutralizing Ab responses by 28 dpi. Intriguingly, SAMHD1 influenced these cell-mediated immune (14 dpi) and neutralizing Ab (28 dpi) responses in male but not female mice. Our findings formally demonstrate SAMHD1 as an antiretroviral factor in vivo that could promote adaptive immune responses in a sex-dependent manner. The requirement for LPS to unravel the SAMHD1 immunological phenotype suggests that comorbidities associated with a "leaky" gut barrier may influence the antiviral function of SAMHD1 in vivo.
Assuntos
Imunidade Adaptativa/imunologia , Vírus da Leucemia Murina de Friend/crescimento & desenvolvimento , Lipopolissacarídeos/farmacologia , Infecções por Retroviridae/prevenção & controle , Proteína 1 com Domínio SAM e Domínio HD/genética , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Apresentação de Antígeno/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , DNA Viral/sangue , Feminino , Vírus da Leucemia Murina de Friend/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Retroviridae/virologia , Transcrição Reversa/genética , Proteína 1 com Domínio SAM e Domínio HD/imunologia , Carga ViralRESUMO
Type 2 diabetes is an established risk factor for tuberculosis, but the underlying mechanisms are largely unknown. We established an in vitro model to analyze the effect of high glucose concentrations in antigen processing and presentation in antigen-presenting cells. Human monocyte-derived macrophages (MDMs) were exposed to high (11 mM and 30 mM) and low (5.5 mM) glucose concentrations and infected with Mycobacterium tuberculosis (Mtb). Flow cytometry was used to analyze the effect of high glucose concentrations in histocompatibility complex (MHC) class II molecules (HLA-DR) and co-stimulatory molecules (CD80 and CD86), indispensable for an adequate antigenic presentation and CD4+ T cell activation. HLA-DR and CD86 were significantly decreased by high glucose concentrations compared with low glucose concentrations. Confocal microscopy was used to detect Rab 5 and Lamp-1, proteins involved in the kinetics of antigen processing as early markers, and Rab 7 and cathepsin D as late markers. We observed a delay in the dynamics of the acquisition of Rab 7 and cathepsin D in high glucose concentrations. Moreover, the kinetics of the formation M. tuberculosis peptide-MHC II complexes in MDMs was decreased under high glucose concentrations, reducing their capacity for T cell activation. These findings suggest that high glucose concentrations directly affect antigenic processing, and therefore antigenic presentation.
Assuntos
Antígeno B7-2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Glucose/efeitos adversos , Antígenos HLA-DR/metabolismo , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Bactérias/metabolismo , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Regulação para Baixo , Citometria de Fluxo , Humanos , Macrófagos/microbiologia , Modelos BiológicosRESUMO
INTRODUCTION: Lipid droplets (LDs) are dynamic and evolutionary conserved lipid-enriched organelles composed of a core of neutral lipids surrounded by a monolayer of phospholipids associated with a diverse array of proteins that are cell- and stimulus-regulated. Far beyond being simply a deposit of neutral lipids, accumulating evidence demonstrate that LDs act as spatial and temporal local for lipid and protein compartmentalization and signaling organization. AREAS COVERED: This review focuses on the progress in our understanding of LD protein diversity and LD functions in the context of cell signaling and immune responses, highlighting the relationship between LD composition with the multiple roles of this organelle in immunometabolism, inflammation and host-response to infection. EXPERT OPINION: LDs are essential platforms for various cellular processes, including metabolic regulation, cell signaling, and immune responses. The functions of LD in infection and inflammatory disease are associated with the dynamic and complexity of their proteome. Our contemporary view place LDs as critical regulators of different inflammatory and infectious diseases and key markers of leukocyte activation.