RESUMO
Intracellular pathogens pose a significant threat to animals. In defense, innate immune sensors attempt to detect these pathogens using pattern recognition receptors that either directly detect microbial molecules or indirectly detect their pathogenic activity. These sensors trigger different forms of regulated cell death, including pyroptosis, apoptosis, and necroptosis, which eliminate the infected host cell niche while simultaneously promoting beneficial immune responses. These defenses force intracellular pathogens to evolve strategies to minimize or completely evade the sensors. In this review, we discuss recent advances in our understanding of the cytosolic pattern recognition receptors that drive cell death, including NLRP1, NLRP3, NLRP6, NLRP9, NLRC4, AIM2, IFI16, and ZBP1.
Assuntos
Inflamassomos , Piroptose , Animais , Apoptose , Morte Celular , Humanos , Inflamassomos/metabolismo , NecroptoseRESUMO
Infection with Mycobacterium tuberculosis causes >1.5 million deaths worldwide annually. Innate immune cells are the first to encounter M. tuberculosis, and their response dictates the course of infection. Dendritic cells (DCs) activate the adaptive response and determine its characteristics. Macrophages are responsible both for exerting cell-intrinsic antimicrobial control and for initiating and maintaining inflammation. The inflammatory response to M. tuberculosis infection is a double-edged sword. While cytokines such as TNF-α and IL-1 are important for protection, either excessive or insufficient cytokine production results in progressive disease. Furthermore, neutrophils-cells normally associated with control of bacterial infection-are emerging as key drivers of a hyperinflammatory response that results in host mortality. The roles of other innate cells, including natural killer cells and innate-like T cells, remain enigmatic. Understanding the nuances of both cell-intrinsic control of infection and regulation of inflammation will be crucial for the successful development of host-targeted therapeutics and vaccines.
Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Citocinas , Humanos , Imunidade Inata , MacrófagosRESUMO
Retroviruses are genome invaders that have shared a long history of coevolution with vertebrates and their immune system. Found endogenously in genomes as traces of past invasions, retroviruses are also considerable threats to human health when they exist as exogenous viruses such as HIV. The immune response to retroviruses is engaged by germline-encoded sensors of innate immunity that recognize viral components and damage induced by the infection. This response develops with the induction of antiviral effectors and launching of the clonal adaptive immune response, which can contribute to protective immunity. However, retroviruses efficiently evade the immune response, owing to their rapid evolution. The failure of specialized immune cells to respond, a form of neglect, may also contribute to inadequate antiretroviral immune responses. Here, we discuss the mechanisms by which immune responses to retroviruses are mounted at the molecular, cellular, and organismal levels. We also discuss how intrinsic, innate, and adaptive immunity may cooperate or conflict during the generation of immune responses.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Infecções por Retroviridae/imunologia , Infecções por Retroviridae/virologia , Retroviridae/imunologia , Imunidade Adaptativa , Animais , Humanos , Evasão da Resposta Imune , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunidade Inata , Infecções por Retroviridae/metabolismoRESUMO
The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina , Humanos , Transporte Biológico , Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/química , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/ultraestrutura , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/metabolismo , Transmissão Sináptica , Imidazóis/química , Sarcosina/análogos & derivados , Piperidinas/químicaRESUMO
Plant diseases cause famines, drive human migration, and present challenges to agricultural sustainability as pathogen ranges shift under climate change. Plant breeders discovered Mendelian genetic loci conferring disease resistance to specific pathogen isolates over 100 years ago. Subsequent breeding for disease resistance underpins modern agriculture and, along with the emergence and focus on model plants for genetics and genomics research, has provided rich resources for molecular biological exploration over the last 50 years. These studies led to the identification of extracellular and intracellular receptors that convert recognition of extracellular microbe-encoded molecular patterns or intracellular pathogen-delivered virulence effectors into defense activation. These receptor systems, and downstream responses, define plant immune systems that have evolved since the migration of plants to land â¼500 million years ago. Our current understanding of plant immune systems provides the platform for development of rational resistance enhancement to control the many diseases that continue to plague crop production.
Assuntos
Resistência à Doença , Doenças das Plantas , Imunidade Vegetal , Plantas , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Plantas/imunologia , Plantas/genética , Resistência à Doença/genética , HumanosRESUMO
Innate immune responses to microbial pathogens are regulated by intracellular receptors known as nucleotide-binding leucine-rich repeat receptors (NLRs) in both the plant and animal kingdoms. Across plant innate immune systems, "helper" NLRs (hNLRs) work in coordination with "sensor" NLRs (sNLRs) to modulate disease resistance signaling pathways. Activation mechanisms of hNLRs based on structures are unknown. Our research reveals that the hNLR, known as NLR required for cell death 4 (NRC4), assembles into a hexameric resistosome upon activation by the sNLR Bs2 and the pathogenic effector AvrBs2. This conformational change triggers immune responses by facilitating the influx of calcium ions (Ca2+) into the cytosol. The activation mimic alleles of NRC2, NRC3, or NRC4 alone did not induce Ca2+ influx and cell death in animal cells, suggesting that unknown plant-specific factors regulate NRCs' activation in plants. These findings significantly advance our understanding of the regulatory mechanisms governing plant immune responses.
RESUMO
Galectins are a family of mammalian carbohydrate-binding proteins expressed by many cell types. Galectins can function intracellularly and can also be secreted to bind to cell surface glycoconjugate counterreceptors. Some galectins are made by immune cells, whereas other galectins are secreted by different cell types, such as endothelial or epithelial cells, and bind to immune cells to regulate immune responses. Galectin binding to a single glycan ligand is a low-affinity interaction, but the multivalency of galectins and the glycan ligands presented on cell surface glycoproteins results in high-avidity binding that can reversibly scaffold or cluster these glycoproteins. Galectin binding to a specific glycoprotein counterreceptor is regulated in part by the repertoire of glycosyltransferase enzymes (which make the glycan ligands) expressed by that cell, and the effect of galectin binding results from clustering or retention of specific glycoprotein counterreceptors bearing these specific ligands.
Assuntos
Galectinas/metabolismo , Glicosiltransferases/metabolismo , Imunidade , Animais , Carboidratos/imunologia , Citoesqueleto , Galectinas/imunologia , Glicoproteínas/metabolismo , Humanos , Ligação Proteica , Agregação de ReceptoresRESUMO
Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
Assuntos
Imunidade Inata , Nucleotidiltransferases , Humanos , Animais , Nucleotidiltransferases/metabolismo , Imunidade Inata/genética , Transdução de Sinais/genética , DNA/metabolismo , Receptores de Reconhecimento de PadrãoRESUMO
Enabling and constraining immune activation is of fundamental importance in maintaining cellular homeostasis. Depleting BAK1 and SERK4, the co-receptors of multiple pattern recognition receptors (PRRs), abolishes pattern-triggered immunity but triggers intracellular NOD-like receptor (NLR)-mediated autoimmunity with an elusive mechanism. By deploying RNAi-based genetic screens in Arabidopsis, we identified BAK-TO-LIFE 2 (BTL2), an uncharacterized receptor kinase, sensing BAK1/SERK4 integrity. BTL2 induces autoimmunity through activating Ca2+ channel CNGC20 in a kinase-dependent manner when BAK1/SERK4 are perturbed. To compensate for BAK1 deficiency, BTL2 complexes with multiple phytocytokine receptors, leading to potent phytocytokine responses mediated by helper NLR ADR1 family immune receptors, suggesting phytocytokine signaling as a molecular link connecting PRR- and NLR-mediated immunity. Remarkably, BAK1 constrains BTL2 activation via specific phosphorylation to maintain cellular integrity. Thus, BTL2 serves as a surveillance rheostat sensing the perturbation of BAK1/SERK4 immune co-receptors in promoting NLR-mediated phytocytokine signaling to ensure plant immunity.
Assuntos
Arabidopsis , Imunidade Vegetal , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Reconhecimento de Padrão , Transdução de SinaisRESUMO
The SARS-CoV-2 Omicron variant with increased fitness is spreading rapidly worldwide. Analysis of cryo-EM structures of the spike (S) from Omicron reveals amino acid substitutions forging interactions that stably maintain an active conformation for receptor recognition. The relatively more compact domain organization confers improved stability and enhances attachment but compromises the efficiency of the viral fusion step. Alterations in local conformation, charge, and hydrophobic microenvironments underpin the modulation of the epitopes such that they are not recognized by most NTD- and RBD-antibodies, facilitating viral immune escape. Structure of the Omicron S bound with human ACE2, together with the analysis of sequence conservation in ACE2 binding region of 25 sarbecovirus members, as well as heatmaps of the immunogenic sites and their corresponding mutational frequencies, sheds light on conserved and structurally restrained regions that can be used for the development of broad-spectrum vaccines and therapeutics.
Assuntos
Evasão da Resposta Imune/fisiologia , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/química , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/metabolismo , Anticorpos Antivirais/imunologia , Sítios de Ligação , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Microscopia Crioeletrônica , Humanos , Mutagênese Sítio-Dirigida , Testes de Neutralização , Ligação Proteica , Domínios Proteicos/imunologia , Estrutura Quaternária de Proteína , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Ressonância de Plasmônio de Superfície , Ligação ViralRESUMO
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antígenos Virais/imunologia , Candida albicans/química , Mananas/imunologia , Hidróxido de Alumínio/química , Animais , Anticorpos Neutralizantes/imunologia , Especificidade de Anticorpos/imunologia , Linfócitos B/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Chlorocebus aethiops , Epitopos/imunologia , Imunidade Inata , Imunização , Inflamação/patologia , Interferons/metabolismo , Lectinas Tipo C/metabolismo , Ligantes , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Linfonodos/imunologia , Linfonodos/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Seios Paranasais/metabolismo , Subunidades Proteicas/metabolismo , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Solubilidade , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/imunologia , Fator de Transcrição RelB/metabolismo , Células Vero , beta-Glucanas/metabolismoRESUMO
The human monoclonal antibody (HmAb) C10 potently cross-neutralizes Zika virus (ZIKV) and dengue virus. Analysis of antibody fragment (Fab) C10 interactions with ZIKV and dengue virus serotype 2 (DENV2) particles by cryoelectron microscopy (cryo-EM) and amide hydrogen/deuterium exchange mass spectrometry (HDXMS) shows that Fab C10 binding decreases overall ZIKV particle dynamics, whereas with DENV2, the same Fab causes increased dynamics. Testing of different Fab C10:DENV2 E protein molar ratios revealed that, at higher Fab ratios, especially at saturated concentrations, the Fab enhanced viral dynamics (detected by HDXMS), and observation under cryo-EM showed increased numbers of distorted particles. Our results suggest that Fab C10 stabilizes ZIKV but that with DENV2 particles, high Fab C10 occupancy promotes E protein dimer conformational changes leading to overall increased particle dynamics and distortion of the viral surface. This is the first instance of a broadly neutralizing antibody eliciting virus-specific increases in whole virus particle dynamics.
Assuntos
Anticorpos Neutralizantes , Vírus da Dengue , Dengue , Proteínas do Envelope Viral , Infecção por Zika virus , Zika virus , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/imunologia , Reações Cruzadas , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/fisiologia , Humanos , Ligação Proteica , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/imunologia , Proteínas do Envelope Viral/metabolismo , Zika virus/imunologia , Zika virus/fisiologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologiaRESUMO
Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens.
Assuntos
Fatores Imunológicos/farmacologia , RNA/farmacologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Antígenos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Proteína DEAD-box 58/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Imunidade/efeitos dos fármacos , Imunocompetência , Memória Imunológica , Imunoterapia , Interferons/metabolismo , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Peptídeos/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Linfócitos T/efeitos dos fármacosRESUMO
Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.
Assuntos
COVID-19/patologia , Interferons/metabolismo , Sistema Respiratório/virologia , Índice de Gravidade de Doença , Fatores Etários , Envelhecimento/patologia , COVID-19/genética , COVID-19/imunologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Regulação da Expressão Gênica , Humanos , Interferons/genética , Leucócitos/patologia , Leucócitos/virologia , Pulmão/patologia , Pulmão/virologia , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Carga ViralRESUMO
Recognition of microbe-associated molecular patterns (MAMPs) is crucial for the plant's immune response. How this sophisticated perception system can be usefully deployed in roots, continuously exposed to microbes, remains a mystery. By analyzing MAMP receptor expression and response at cellular resolution in Arabidopsis, we observed that differentiated outer cell layers show low expression of pattern-recognition receptors (PRRs) and lack MAMP responsiveness. Yet, these cells can be gated to become responsive by neighbor cell damage. Laser ablation of small cell clusters strongly upregulates PRR expression in their vicinity, and elevated receptor expression is sufficient to induce responsiveness in non-responsive cells. Finally, localized damage also leads to immune responses to otherwise non-immunogenic, beneficial bacteria. Damage-gating is overridden by receptor overexpression, which antagonizes colonization. Our findings that cellular damage can "switch on" local immune responses helps to conceptualize how MAMP perception can be used despite the presence of microbial patterns in the soil.
Assuntos
Arabidopsis/imunologia , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Raízes de Plantas/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/microbiologia , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/efeitos da radiação , Ascorbato Peroxidases/metabolismo , Ascorbato Peroxidases/efeitos da radiação , Flagelina/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Terapia a Laser/métodos , Proteínas de Membrana/metabolismo , Proteínas de Membrana/efeitos da radiação , Microscopia Confocal , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/microbiologia , Raízes de Plantas/efeitos da radiação , Proteínas Quinases/metabolismo , Proteínas Quinases/efeitos da radiação , Receptores de Reconhecimento de Padrão/efeitos da radiação , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Imagem com Lapso de TempoRESUMO
T cell activation is a critical event in the adaptive immune response, indispensable for cell-mediated and humoral immunity as well as for immune regulation. Recent years have witnessed an emerging trend emphasizing the essential role that physical force and mechanical properties play at the T cell interface. In this review, we integrate current knowledge of T cell antigen recognition and the different models of T cell activation from the perspective of mechanobiology, focusing on the interaction between the T cell receptor (TCR) and the peptide-major histocompatibility complex (pMHC) antigen. We address the shortcomings of TCR affinity alone in explaining T cell functional outcomes and the rising status of force-regulated TCR bond lifetimes, most notably the TCR catch bond. Ultimately, T cell activation and the ensuing physiological responses result from mechanical interaction between TCRs and the pMHC.
Assuntos
Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T , Biofísica , Antígenos de Histocompatibilidade , Complexo Principal de Histocompatibilidade/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos TRESUMO
TLR8 is among the highest-expressed pattern-recognition receptors in the human myeloid compartment, yet its mode of action is poorly understood. TLR8 engages two distinct ligand binding sites to sense RNA degradation products, although it remains unclear how these ligands are formed in cellulo in the context of complex RNA molecule sensing. Here, we identified the lysosomal endoribonuclease RNase T2 as a non-redundant upstream component of TLR8-dependent RNA recognition. RNase T2 activity is required for rendering complex single-stranded, exogenous RNA molecules detectable for TLR8. This is due to RNase T2's preferential cleavage of single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2',3'-cyclophosphate-terminated oligoribonucleotides. Thus-generated molecules constitute agonistic ligands for the first and second binding pocket of TLR8. Together, these results establish the identity and origin of the RNA-derived molecular pattern sensed by TLR8.
Assuntos
Endorribonucleases/metabolismo , Proteólise , Receptor 8 Toll-Like/metabolismo , Motivos de Aminoácidos , Sequência de Bases , Linhagem Celular , Endorribonucleases/deficiência , Humanos , Modelos Moleculares , Monócitos/metabolismo , Células Mieloides/metabolismo , Isótopos de Nitrogênio , Oligonucleotídeos/metabolismo , Purinas/metabolismo , RNA/metabolismo , Staphylococcus aureus/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/química , Uridina/metabolismoRESUMO
Sexually naive animals have to distinguish between the sexes because they show species-typical interactions with males and females without meaningful prior experience. However, central neural pathways in naive mammals that recognize sex of other individuals remain poorly characterized. We examined the role of the principal component of the bed nucleus of stria terminalis (BNSTpr), a limbic center, in social interactions in mice. We find that activity of aromatase-expressing BNSTpr (AB) neurons appears to encode sex of other animals and subsequent displays of mating in sexually naive males. Silencing these neurons in males eliminates preference for female pheromones and abrogates mating success, whereas activating them even transiently promotes male-male mating. Surprisingly, female AB neurons do not appear to control sex recognition, mating, or maternal aggression. In summary, AB neurons represent sex of other animals and govern ensuing social behaviors in sexually naive males.
Assuntos
Sistema Límbico/metabolismo , Núcleos Septais/fisiologia , Comportamento Sexual Animal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Aromatase/metabolismo , Encéfalo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/metabolismo , Neurônios/metabolismo , Feromônios/metabolismo , Caracteres Sexuais , Comportamento SocialRESUMO
T cell recognition of specific antigens mediates protection from pathogens and controls neoplasias, but can also cause autoimmunity. Our knowledge of T cell antigens and their implications for human health is limited by the technical limitations of T cell profiling technologies. Here, we present T-Scan, a high-throughput platform for identification of antigens productively recognized by T cells. T-Scan uses lentiviral delivery of antigen libraries into cells for endogenous processing and presentation on major histocompatibility complex (MHC) molecules. Target cells functionally recognized by T cells are isolated using a reporter for granzyme B activity, and the antigens mediating recognition are identified by next-generation sequencing. We show T-Scan correctly identifies cognate antigens of T cell receptors (TCRs) from viral and human genome-wide libraries. We apply T-Scan to discover new viral antigens, perform high-resolution mapping of TCR specificity, and characterize the reactivity of a tumor-derived TCR. T-Scan is a powerful approach for studying T cell responses.
Assuntos
Antígenos de Neoplasias/imunologia , Epitopos de Linfócito T/imunologia , Genes MHC Classe I/imunologia , Antígenos HLA/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Apresentação de Antígeno/imunologia , Antígenos de Neoplasias/genética , Doadores de Sangue , Linfócitos T CD8-Positivos/metabolismo , Feminino , Técnicas de Inativação de Genes , Genes MHC Classe I/genética , Granzimas/metabolismo , Células HEK293 , Antígenos HLA/genética , Humanos , Proteínas de Neoplasias/genética , Transdução Genética , TransfecçãoRESUMO
The formation of ordered nanostructures by molecular self-assembly of proteins and peptides represents one of the principal directions in nanotechnology. Indeed, polyamides provide superior features as materials with diverse physical properties. A reductionist approach allowed the identification of extremely short peptide sequences, as short as dipeptides, which could form well-ordered amyloid-like ß-sheet-rich assemblies comparable to supramolecular structures made of much larger proteins. Some of the peptide assemblies show remarkable mechanical, optical, and electrical characteristics. Another direction of reductionism utilized a natural noncoded amino acid, α-aminoisobutryic acid, to form short superhelical assemblies. The use of this exceptional helix inducer motif allowed the fabrication of single heptad repeats used in various biointerfaces, including their use as surfactants and DNA-binding agents. Two additional directions of the reductionist approach include the use of peptide nucleic acids (PNAs) and coassembly techniques. The diversified accomplishments of the reductionist approach, as well as the exciting future advances it bears, are discussed.