Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 19.145
Filtrar
1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1167-1170, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798393

RESUMO

OBJECTIVE: To investigate the effect of chidamide on the killing activity of NK (Natural killer cell, NK) cells targeting K562 cells and its related mechanism. METHODS: K562 cells were pretreated with chidamide at different concentrations and cocultured with NK cells at different effect-target ratios. The killing effect of chidamide on K562 cells by NK cells, the expression of natural killer group 2 member D (NKG2D) ligands and apoptosis rate of K562 cells were detected by flow cytometry. RESULTS: The killing sensitivity of NK cells to K562 cells could be enhanced by chidamide. The expression of ULBP2 on K562 cell surface could be up-regulate, however, the expression of ULBP1 and MICA/MICB showed no statistically difference as compared with control group. Chidamide showed no obvious cytotoxicity to K562 cells. CONCLUSION: Chidamide can significantly improve killing efficiency of NK cells on K562 cells, which may be related to the up-regulation of ULBP2 expression.


Assuntos
Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais/imunologia , Aminopiridinas , Benzamidas , Proteínas Ligadas por GPI , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Células K562 , Subfamília K de Receptores Semelhantes a Lectina de Células NK
2.
PLoS Pathog ; 16(8): e1008818, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776973

RESUMO

Leprosy is a chronic disease caused by Mycobacterium leprae. Worldwide, more than 200,000 new patients are affected by leprosy annually, making it the second most common mycobacterial disease after tuberculosis. The MHC/HLA region has been consistently identified as carrying major leprosy susceptibility variants in different populations at times with inconsistent results. To establish the unambiguous molecular identity of classical HLA class I and class II leprosy susceptibility factors, we applied next-generation sequencing to genotype with high-resolution 11 HLA class I and class II genes in 1,155 individuals from a Vietnamese leprosy case-control sample. HLA alleles belonging to an extended haplotype from HLA-A to HLA-DPB1 were associated with risk to leprosy. This susceptibility signal could be reduced to the HLA-DRB1*10:01~ HLA-DQA1*01:05 alleles which were in complete linkage disequilibrium (LD). In addition, haplotypes containing HLA-DRB3~ HLA-DRB1*12:02 and HLA-C*07:06~ HLA-B*44:03~ HLA-DRB1*07:01 alleles were found as two independent protective factors for leprosy. Moreover, we replicated the previously associated HLA-DRB1*15:01 as leprosy risk factor and HLA-DRB1*04:05~HLA-DQA1*03:03 as protective alleles. When we narrowed the analysis to the single amino acid level, we found that the associations of the HLA alleles were largely captured by four independent amino acids at HLA-DRß1 positions 57 (D) and 13 (F), HLA-B position 63 (E) and HLA-A position 19 (K). Hence, analyses at the amino acid level circumvented the ambiguity caused by strong LD of leprosy susceptibility HLA alleles and identified four distinct leprosy susceptibility factors.


Assuntos
Aminoácidos/genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Hanseníase/patologia , Mutação , Adolescente , Adulto , Feminino , Haplótipos , Humanos , Hanseníase/genética , Masculino , Adulto Jovem
3.
Science ; 369(6506): 936-942, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820119

RESUMO

Intestinal microbiota have been proposed to induce commensal-specific memory T cells that cross-react with tumor-associated antigens. We identified major histocompatibility complex (MHC) class I-binding epitopes in the tail length tape measure protein (TMP) of a prophage found in the genome of the bacteriophage Enterococcus hirae Mice bearing E. hirae harboring this prophage mounted a TMP-specific H-2Kb-restricted CD8+ T lymphocyte response upon immunotherapy with cyclophosphamide or anti-PD-1 antibodies. Administration of bacterial strains engineered to express the TMP epitope improved immunotherapy in mice. In renal and lung cancer patients, the presence of the enterococcal prophage in stools and expression of a TMP-cross-reactive antigen by tumors correlated with long-term benefit of PD-1 blockade therapy. In melanoma patients, T cell clones recognizing naturally processed cancer antigens that are cross-reactive with microbial peptides were detected.


Assuntos
Antígenos de Neoplasias/imunologia , Bacteriófagos/imunologia , Streptococcus faecium ATCC 9790/virologia , Microbioma Gastrointestinal/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunoterapia/métodos , Neoplasias/terapia , Proteínas da Cauda Viral/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Alquilantes/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Reações Cruzadas , Ciclofosfamida/uso terapêutico , Epitopos/imunologia , Fezes/virologia , Antígenos H-2/imunologia , Humanos , Camundongos , Neoplasias/dietoterapia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Proteínas da Cauda Viral/uso terapêutico
4.
Cells ; 9(9)2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32859121

RESUMO

Natural killer cells are important in the control of viral infections. However, the role of NK cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has previously not been identified. Peripheral blood NK cells from SARS-CoV and SARS-CoV-2 naïve subjects were evaluated for their activation, degranulation, and interferon-gamma expression in the presence of SARS-CoV and SARS-CoV-2 spike proteins. K562 and lung epithelial cells were transfected with spike proteins and co-cultured with NK cells. The analysis was performed by flow cytometry and immune fluorescence. SARS-CoV and SARS-CoV-2 spike proteins did not alter NK cell activation in a K562 in vitro model. On the contrary, SARS-CoV-2 spike 1 protein (SP1) intracellular expression by lung epithelial cells resulted in NK cell-reduced degranulation. Further experiments revealed a concomitant induction of HLA-E expression on the surface of lung epithelial cells and the recognition of an SP1-derived HLA-E-binding peptide. Simultaneously, there was increased modulation of the inhibitory receptor NKG2A/CD94 on NK cells when SP1 was expressed in lung epithelial cells. We ruled out the GATA3 transcription factor as being responsible for HLA-E increased levels and HLA-E/NKG2A interaction as implicated in NK cell exhaustion. We show for the first time that NK cells are affected by SP1 expression in lung epithelial cells via HLA-E/NKG2A interaction. The resulting NK cells' exhaustion might contribute to immunopathogenesis in SARS-CoV-2 infection.


Assuntos
Betacoronavirus/química , Infecções por Coronavirus/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Ativação Linfocitária/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Doadores de Sangue , Brônquios/citologia , Degranulação Celular/genética , Técnicas de Cocultura , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Células Epiteliais/metabolismo , Humanos , Interferon gama/metabolismo , Células K562 , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , RNA Viral/genética , Vírus da SARS/química , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/metabolismo , Síndrome Respiratória Aguda Grave/virologia , Glicoproteína da Espícula de Coronavírus/genética , Transfecção
5.
Clin Immunol ; 219: 108572, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32810602

RESUMO

Human Leukocyte Antigen (HLA) includes a large set of genes with important actions in immune response against viral infection. Numerous studies have revealed the existence of significant associations between certain HLA alleles and the susceptibility and prognosis of different infectious diseases. In this pilot study we analyse the binding affinity between 66 class I HLA alleles and SARS-CoV-2 viral peptides, and its association with the severity of the disease. A total of 45 Spanish patients with mild, moderate and severe SARS-CoV-2 infection were typed for HLA class I; after that, we analysed if an in silico model of HLA I-viral peptide binding affinity and classical HLA supertypes could be correlated to the severity of the disease. Our results suggest that patients with mild disease present Class I HLA molecules with a higher theoretical capacity for binding SARS-Cov-2 peptides and showed greater heterozygosity when comparing them with moderate and severe groups. In this regard, identifying HLA-SARS-CoV-2 peptides binding differences between individuals would help to clarify the heterogeneity of clinical responses to the disease and will also be useful to guide a personalized treatment according to its particular risk.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/genética , Antígenos de Histocompatibilidade Classe I/genética , Interações Hospedeiro-Patógeno/imunologia , Pneumonia Viral/genética , Proteínas Virais/genética , Adulto , Idoso , Alelos , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Progressão da Doença , Feminino , Expressão Gênica , Frequência do Gene , Antígenos de Histocompatibilidade Classe I/classificação , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Pandemias , Peptídeos/genética , Peptídeos/imunologia , Projetos Piloto , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Ligação Proteica , Índice de Gravidade de Doença , Espanha , Proteínas Virais/imunologia
6.
Crit Rev Immunol ; 40(2): 173-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749095

RESUMO

Mucosa-associated invariant T cells (MAIT cells) are unconventional, innate-like T lymphocytes with remarkable effector and immunoregulatory functions. They are abundant in the human peripheral blood and also enriched in mucosal layers and in the lungs, SARS-CoV-2's main ports of entry. Once activated, MAIT cells produce inflammatory cytokines and cytolytic effector molecules quickly and copiously. MAIT cells are best known for their antibacterial and antifungal properties. However, they are also activated during viral infections, typically in a cytokine-dependent manner, which may promote antiviral immunity. On the other hand, it is plausible to assume active roles for MAIT cells in infection-provoked cytokine storms and tissue damage. SARS-CoV-2 infection may be asymptomatic, mild, severe, or even fatal, depending on sex, age, the presence of preexisting morbidities, and the individual's immunological competence, or lack thereof, among other factors. Based on the available literature, I propose that MAIT cells regulate the host response to SARS-CoV-2 and constitute attractive targets in the prevention or clinical management of coronavirus disease 19 (COVID-19) and some of its complications. Unlike mainstream T cells, MAIT cells are restricted by a monomorphic antigen-presenting molecule called MHC-related protein 1 (MR1). Therefore, MR1 ligands should modify MAIT cell functions relatively uniformly in genetically diverse subjects and may be tested as immunotherapeutic agents or vaccine adjuvants in future studies.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariáveis Associadas à Mucosa/imunologia , Pneumonia Viral/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/patologia , Citocinas/imunologia , Humanos , Células T Invariáveis Associadas à Mucosa/metabolismo , Pandemias , Pneumonia Viral/patologia
7.
Int J Infect Dis ; 98: 454-459, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32693089

RESUMO

Genetic factors such as the HLA type of patients may play a role in regard to disease severity and clinical outcome of patients with COVID-19. Taking the data deposited in the GISAID database, we made predictions using the IEDB analysis resource (TepiTool) to gauge how variants in the SARS-CoV-2 genome may change peptide binding to the most frequent MHC-class I and -II alleles in Africa, Asia and Europe. We caracterized how a single mutation in the wildtype sequence of of SARS-CoV-2 could influence the peptide binding of SARS-CoV-2 variants to MHC class II, but not to MHC class I alleles. Assuming the ORF8 (L84S) mutation is biologically significant, selective pressure from MHC class II alleles may select for viral varients and subsequently shape the quality and quantity of cellular immune responses aginast SARS-CoV-2. MHC 4-digit typing along with viral sequence analysis should be considered in studies examining clinical outcomes in patients with COVID-19.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/mortalidade , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Pneumonia Viral/genética , Pneumonia Viral/mortalidade , África , Alelos , Ásia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Europa (Continente) , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
8.
Cell Syst ; 11(2): 131-144.e6, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32721383

RESUMO

We present a combinatorial machine learning method to evaluate and optimize peptide vaccine formulations for SARS-CoV-2. Our approach optimizes the presentation likelihood of a diverse set of vaccine peptides conditioned on a target human-population HLA haplotype distribution and expected epitope drift. Our proposed SARS-CoV-2 MHC class I vaccine formulations provide 93.21% predicted population coverage with at least five vaccine peptide-HLA average hits per person (≥ 1 peptide: 99.91%) with all vaccine peptides perfectly conserved across 4,690 geographically sampled SARS-CoV-2 genomes. Our proposed MHC class II vaccine formulations provide 97.21% predicted coverage with at least five vaccine peptide-HLA average hits per person with all peptides having an observed mutation probability of ≤ 0.001. We provide an open-source implementation of our design methods (OptiVax), vaccine evaluation tool (EvalVax), as well as the data used in our design efforts here: https://github.com/gifford-lab/optivax.


Assuntos
Betacoronavirus/imunologia , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Análise de Sequência de DNA/métodos , Vacinas de Subunidades/imunologia , Vacinas Virais/imunologia , Betacoronavirus/genética , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Aprendizado de Máquina , Análise de Sequência de DNA/normas , Vacinas de Subunidades/química , Vacinas de Subunidades/genética , Vacinas Virais/química , Vacinas Virais/genética
9.
BMC Bioinformatics ; 21(1): 295, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32640979

RESUMO

BACKGROUND: The human leukocyte antigen (HLA) gene family plays a key role in the immune response and thus is crucial in many biomedical and clinical settings. Utilizing Sanger sequencing, the golden standard technology for HLA typing enables accurate identification of HLA alleles in high-resolution. However, only the commercial software, such as uTYPE, SBT-Assign, and SBTEngine, and very few open-source tools could be applied to perform HLA typing based on Sanger sequencing. RESULTS: We developed a user-friendly, cross-platform and open-source desktop application, known as SOAPTyping, for Sanger-based typing in HLA class I and II alleles. SOAPTyping can produce accurate results with a comprehensible protocol and featured functions. Moreover, SOAPTyping supports a more advanced group-specific sequencing primers (GSSP) module to solve the ambiguous typing results. We used SOAPTyping to analyze 36 samples with known HLA typing from the University of California Los Angeles (UCLA) International HLA DNA Exchange platform and 100 anonymous clinical samples, and the HLA typing results from SOAPTyping are identical to the golden results and 5.5 times faster than commercial software uTYPE, which shows the usability of SOAPTyping. CONCLUSIONS: We introduce the SOAPTyping as the first open-source and cross-platform HLA typing software with the capability of producing high-resolution HLA typing predictions from Sanger sequence data.


Assuntos
Antígenos HLA/genética , Teste de Histocompatibilidade/métodos , Análise de Sequência de DNA , Software , Alelos , Primers do DNA , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Classe II , Humanos
10.
BMC Bioinformatics ; 21(1): 279, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32615972

RESUMO

BACKGROUND: Immunotherapy is a promising route towards personalized cancer treatment. A key algorithmic challenge in this process is to decide if a given peptide (neoepitope) binds with the major histocompatibility complex (MHC). This is an active area of research and there are many MHC binding prediction algorithms that can predict the MHC binding affinity for a given peptide to a high degree of accuracy. However, most of the state-of-the-art approaches make use of complicated training and model selection procedures, are restricted to peptides of a certain length and/or rely on heuristics. RESULTS: We put forward USMPep, a simple recurrent neural network that reaches state-of-the-art approaches on MHC class I binding prediction with a single, generic architecture and even a single set of hyperparameters both on IEDB benchmark datasets and on the very recent HPV dataset. Moreover, the algorithm is competitive for a single model trained from scratch, while ensembling multiple regressors and language model pretraining can still slightly improve the performance. The direct application of the approach to MHC class II binding prediction shows a solid performance despite of limited training data. CONCLUSIONS: We demonstrate that competitive performance in MHC binding affinity prediction can be reached with a standard architecture and training procedure without relying on any heuristics.


Assuntos
Algoritmos , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Modelos Genéticos , Alelos , Área Sob a Curva , Sequência de Bases , Bases de Dados Genéticas , Humanos , Peptídeos/metabolismo , Ligação Proteica , Curva ROC
13.
Immunogenetics ; 72(5): 295-304, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32577798

RESUMO

Tumor-specific neoantigens are mutated self-peptides presented by tumor cell major histocompatibility complex (MHC) molecules and are necessary to elicit host's anti-cancer cytotoxic T cell responses. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs). However, current wet-lab assays for identifying peptide MHC binding are too expensive and time-consuming to meet the clinical needs. In this study, we developed an in silico method with a deep convolutional neural network (CNN) model, iConMHC, to predict peptide MHC binding affinity. Unlike other in silico methods that only learn from properties of amino acid in neoantigen peptides alone and/or MHCs alone, iConMHC learns from physical and chemical interaction properties between pairwise amino acids from the two molecules. These properties, such as contact potentials and distances in folded proteins, directly affect neoantigen-MHC binding affinity. In addition, IConMHC is a pan-allele model that is capable of making predictions for all the MHC alleles. Even for those rare MHC alleles without training data, iConMHC can make predictions with reasonable accuracy. We benchmarked iConMHC with other commonly used MHC-I binding predictors and found our model performs better than most of the pan-allele models.


Assuntos
Aprendizado Profundo , Antígenos de Histocompatibilidade Classe I/metabolismo , Peptídeos/metabolismo , Alelos , Sequência de Aminoácidos , Antígenos de Neoplasias/química , Antígenos de Neoplasias/metabolismo , Simulação por Computador , Bases de Dados de Proteínas , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Redes Neurais de Computação , Peptídeos/química , Ligação Proteica , Reprodutibilidade dos Testes
14.
Nat Commun ; 11(1): 2760, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488085

RESUMO

Peptides bound to class I major histocompatibility complexes (MHC) play a critical role in immune cell recognition and can trigger an antitumor immune response in cancer. Surface MHC levels can be modulated by anticancer agents, altering immunity. However, understanding the peptide repertoire's response to treatment remains challenging and is limited by quantitative mass spectrometry-based strategies lacking normalization controls. We describe an experimental platform that leverages recombinant heavy isotope-coded peptide MHCs (hipMHCs) and multiplex isotope tagging to quantify peptide repertoire alterations using low sample input. HipMHCs improve quantitative accuracy of peptide repertoire changes by normalizing for variation across analyses and enable absolute quantification using internal calibrants to determine copies per cell of MHC antigens, which can inform immunotherapy design. Applying this platform in melanoma cell lines to profile the immunopeptidome response to CDK4/6 inhibition and interferon-γ - known modulators of antigen presentation - uncovers treatment-specific alterations, connecting the intracellular response to extracellular immune presentation.


Assuntos
Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Apresentação do Antígeno , Antígenos , Linhagem Celular , Humanos , Imunoterapia , Interferon gama/farmacologia , Espectrometria de Massas , Peptídeos/imunologia , Proteômica
15.
Proc Natl Acad Sci U S A ; 117(27): 15902-15910, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571951

RESUMO

Neurotropic strains of mouse hepatitis virus (MHV), a coronavirus, cause acute and chronic demyelinating encephalomyelitis with similarities to the human disease multiple sclerosis. Here, using a lineage-tracking system, we show that some cells, primarily oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs), survive the acute MHV infection, are associated with regions of demyelination, and persist in the central nervous system (CNS) for at least 150 d. These surviving OLs express major histocompatibility complex (MHC) class I and other genes associated with an inflammatory response. Notably, the extent of inflammatory cell infiltration was variable, dependent on anatomic location within the CNS, and without obvious correlation with numbers of surviving cells. We detected more demyelination in regions with larger numbers of T cells and microglia/macrophages compared to those with fewer infiltrating cells. Conversely, in regions with less inflammation, these previously infected OLs more rapidly extended processes, consistent with normal myelinating function. Together, these results show that OLs are inducers as well as targets of the host immune response and demonstrate how a CNS infection, even after resolution, can induce prolonged inflammatory changes with CNS region-dependent impairment in remyelination.


Assuntos
Sistema Nervoso Central/imunologia , Infecções por Coronavirus/complicações , Doenças Desmielinizantes/etiologia , Oligodendroglia/imunologia , Animais , Infecções por Coronavirus/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Proteínas Luminescentes , Masculino , Camundongos , Vírus da Hepatite Murina , Oligodendroglia/metabolismo
16.
J Hum Genet ; 65(7): 569-575, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: covidwho-185840

RESUMO

To control and prevent the current COVID-19 pandemic, the development of novel vaccines is an emergent issue. In addition, we need to develop tools that can measure/monitor T-cell and B-cell responses to know how our immune system is responding to this deleterious virus. However, little information is currently available about the immune target epitopes of novel coronavirus (SARS-CoV-2) to induce host immune responses. Through a comprehensive bioinformatic screening of potential epitopes derived from the SARS-CoV-2 sequences for HLAs commonly present in the Japanese population, we identified 2013 and 1399 possible peptide epitopes that are likely to have the high affinity (<0.5%- and 2%-rank, respectively) to HLA class I and II molecules, respectively, that may induce CD8+ and CD4+ T-cell responses. These epitopes distributed across the structural (spike, envelope, membrane, and nucleocapsid proteins) and the nonstructural proteins (proteins corresponding to six open reading frames); however, we found several regions where high-affinity epitopes were significantly enriched. By comparing the sequences of these predicted T cell epitopes to the other coronaviruses, we identified 781 HLA-class I and 418 HLA-class II epitopes that have high homologies to SARS-CoV. To further select commonly-available epitopes that would be applicable to larger populations, we calculated population coverages based on the allele frequencies of HLA molecules, and found 2 HLA-class I epitopes covering 83.8% of the Japanese population. The findings in the current study provide us valuable information to design widely-available vaccine epitopes against SARS-CoV-2 and also provide the useful information for monitoring T-cell responses.


Assuntos
Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Betacoronavirus/imunologia , Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito T/química , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Mutação , Fases de Leitura Aberta , Vírus da SARS/imunologia , Vacinas Virais/imunologia
17.
Nature ; 581(7806): 100-105, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32376951

RESUMO

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Assuntos
Adenocarcinoma/imunologia , Autofagia/imunologia , Carcinoma Ductal Pancreático/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Neoplasias Pancreáticas/imunologia , Evasão Tumoral/imunologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Apresentação do Antígeno/imunologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/imunologia , Linhagem Celular Tumoral , Cloroquina/farmacologia , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Masculino , Camundongos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Evasão Tumoral/efeitos dos fármacos
18.
Proc Natl Acad Sci U S A ; 117(23): 12961-12968, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32444487

RESUMO

Viral immune evasion is currently understood to focus on deflecting CD8 T cell recognition of infected cells by disrupting antigen presentation pathways. We evaluated viral interference with the ultimate step in cytotoxic T cell function, the death of infected cells. The viral inhibitor of caspase-8 activation (vICA) conserved in human cytomegalovirus (HCMV) and murine CMV (MCMV) prevents the activation of caspase-8 and proapoptotic signaling. We demonstrate the key role of vICA from either virus, in deflecting antigen-specific CD8 T cell-killing of infected cells. vICA-deficient mutants, lacking either UL36 or M36, exhibit greater susceptibility to CD8 T cell control than mutants lacking the set of immunoevasins known to disrupt antigen presentation via MHC class I. This difference is evident during infection in the natural mouse host infected with MCMV, in settings where virus-specific CD8 T cells are adoptively transferred. Finally, we identify the molecular mechanism through which vICA acts, demonstrating the central contribution of caspase-8 signaling at a point of convergence of death receptor-induced apoptosis and perforin/granzyme-dependent cytotoxicity.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Evasão da Resposta Imune , Linfócitos T Citotóxicos/imunologia , Animais , Apoptose/imunologia , Caspase 8/genética , Caspase 8/metabolismo , Linhagem Celular , Técnicas de Cocultura , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/virologia , Modelos Animais de Doenças , Fibroblastos , Granzimas/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Camundongos , Camundongos Knockout , Muromegalovirus/genética , Muromegalovirus/imunologia , Muromegalovirus/metabolismo , Mutagênese , Perforina/genética , Perforina/metabolismo , Receptores de Morte Celular/metabolismo , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Imagem com Lapso de Tempo , Proteínas Virais/genética , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
19.
J Hum Genet ; 65(7): 569-575, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32372051

RESUMO

To control and prevent the current COVID-19 pandemic, the development of novel vaccines is an emergent issue. In addition, we need to develop tools that can measure/monitor T-cell and B-cell responses to know how our immune system is responding to this deleterious virus. However, little information is currently available about the immune target epitopes of novel coronavirus (SARS-CoV-2) to induce host immune responses. Through a comprehensive bioinformatic screening of potential epitopes derived from the SARS-CoV-2 sequences for HLAs commonly present in the Japanese population, we identified 2013 and 1399 possible peptide epitopes that are likely to have the high affinity (<0.5%- and 2%-rank, respectively) to HLA class I and II molecules, respectively, that may induce CD8+ and CD4+ T-cell responses. These epitopes distributed across the structural (spike, envelope, membrane, and nucleocapsid proteins) and the nonstructural proteins (proteins corresponding to six open reading frames); however, we found several regions where high-affinity epitopes were significantly enriched. By comparing the sequences of these predicted T cell epitopes to the other coronaviruses, we identified 781 HLA-class I and 418 HLA-class II epitopes that have high homologies to SARS-CoV. To further select commonly-available epitopes that would be applicable to larger populations, we calculated population coverages based on the allele frequencies of HLA molecules, and found 2 HLA-class I epitopes covering 83.8% of the Japanese population. The findings in the current study provide us valuable information to design widely-available vaccine epitopes against SARS-CoV-2 and also provide the useful information for monitoring T-cell responses.


Assuntos
Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Betacoronavirus/imunologia , Coronavirus/genética , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito T/química , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Mutação , Fases de Leitura Aberta , Vírus da SARS/imunologia , Vacinas Virais/imunologia
20.
PLoS Comput Biol ; 16(5): e1007757, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453790

RESUMO

T cell epitope candidates are commonly identified using computational prediction tools in order to enable applications such as vaccine design, cancer neoantigen identification, development of diagnostics and removal of unwanted immune responses against protein therapeutics. Most T cell epitope prediction tools are based on machine learning algorithms trained on MHC binding or naturally processed MHC ligand elution data. The ability of currently available tools to predict T cell epitopes has not been comprehensively evaluated. In this study, we used a recently published dataset that systematically defined T cell epitopes recognized in vaccinia virus (VACV) infected C57BL/6 mice (expressing H-2Db and H-2Kb), considering both peptides predicted to bind MHC or experimentally eluted from infected cells, making this the most comprehensive dataset of T cell epitopes mapped in a complex pathogen. We evaluated the performance of all currently publicly available computational T cell epitope prediction tools to identify these major epitopes from all peptides encoded in the VACV proteome. We found that all methods were able to improve epitope identification above random, with the best performance achieved by neural network-based predictions trained on both MHC binding and MHC ligand elution data (NetMHCPan-4.0 and MHCFlurry). Impressively, these methods were able to capture more than half of the major epitopes in the top N = 277 predictions within the N = 767,788 predictions made for distinct peptides of relevant lengths that can theoretically be encoded in the VACV proteome. These performance metrics provide guidance for immunologists as to which prediction methods to use, and what success rates are possible for epitope predictions when considering a highly controlled system of administered immunizations to inbred mice. In addition, this benchmark was implemented in an open and easy to reproduce format, providing developers with a framework for future comparisons against new tools.


Assuntos
Alergia e Imunologia/normas , Epitopos de Linfócito T/imunologia , Antígenos de Histocompatibilidade Classe I/química , Algoritmos , Alelos , Animais , Área Sob a Curva , Automação , Epitopos de Linfócito T/química , Sistema Imunitário , Ligantes , Aprendizado de Máquina , Camundongos , Camundongos Endogâmicos C57BL , Redes Neurais de Computação , Peptídeos/química , Ligação Proteica , Proteoma , Curva ROC , Vírus Vaccinia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA