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2.
Nat Commun ; 12(1): 4699, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349111

RESUMO

Similarity in T-cell receptor (TCR) sequences implies shared antigen specificity between receptors, and could be used to discover novel therapeutic targets. However, existing methods that cluster T-cell receptor sequences by similarity are computationally inefficient, making them impractical to use on the ever-expanding datasets of the immune repertoire. Here, we developed GIANA (Geometric Isometry-based TCR AligNment Algorithm) a computationally efficient tool for this task that provides the same level of clustering specificity as TCRdist at 600 times its speed, and without sacrificing accuracy. GIANA also allows the rapid query of large reference cohorts within minutes. Using GIANA to cluster large-scale TCR datasets provides candidate disease-specific receptors, and provides a new solution to repertoire classification. Querying unseen TCR-seq samples against an existing reference differentiates samples from patients across various cohorts associated with cancer, infectious and autoimmune disease. Our results demonstrate how GIANA could be used as the basis for a TCR-based non-invasive multi-disease diagnostic platform.


Assuntos
Algoritmos , Receptores de Antígenos de Linfócitos T/classificação , COVID-19/diagnóstico , COVID-19/imunologia , Análise por Conglomerados , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/imunologia , Diagnóstico Diferencial , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Humanos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/imunologia , Neoplasias/diagnóstico , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2 , Alinhamento de Sequência
3.
J Immunol ; 207(4): 1180-1193, 2021 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-34341170

RESUMO

Hepatitis C virus (HCV) infection resolves spontaneously in ∼25% of acutely infected humans where viral clearance is mediated primarily by virus-specific CD8+ T cells. Previous cross-sectional analysis of the CD8+ TCR repertoire targeting two immunodominant HCV epitopes reported widespread use of public TCRs shared by different subjects, irrespective of infection outcome. However, little is known about the evolution of the public TCR repertoire during acute HCV and whether cross-reactivity to other Ags can influence infectious outcome. In this article, we analyzed the CD8+ TCR repertoire specific to the immunodominant and cross-reactive HLA-A2-restricted nonstructural 3-1073 epitope during acute HCV in humans progressing to either spontaneous resolution or chronic infection and at ∼1 y after viral clearance. TCR repertoire diversity was comparable among all groups with preferential usage of the TCR-ß V04 and V06 gene families. We identified a set of 13 public clonotypes in HCV-infected humans independent of infection outcome. Six public clonotypes used the V04 gene family. Several public clonotypes were long-lived in resolvers and expanded on reinfection. By mining publicly available data, we identified several low-frequency CDR3 sequences in the HCV-specific repertoire matching human TCRs specific for other HLA-A2-restricted epitopes from melanoma, CMV, influenza A, EBV, and yellow fever viruses, but they were of low frequency and limited cross-reactivity. In conclusion, we identified 13 new public human CD8+ TCR clonotypes unique to HCV that expanded during acute infection and reinfection. The low frequency of cross-reactive TCRs suggests that they are not major determinants of infectious outcome.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Reinfecção/imunologia , Células Clonais/imunologia , Estudos Transversais , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
4.
Nat Commun ; 12(1): 4844, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381053

RESUMO

Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease.


Assuntos
Antígenos CD1/imunologia , Glicoproteínas/imunologia , Leucemia/imunologia , Lisofosfolipídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Doadores de Tecidos , Animais , Apresentação do Antígeno , Antígenos CD1/metabolismo , Glicoproteínas/metabolismo , Humanos , Imunoterapia Adotiva , Leucemia/metabolismo , Leucemia/terapia , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Nat Commun ; 12(1): 4515, 2021 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312385

RESUMO

The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.


Assuntos
COVID-19/imunologia , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , COVID-19/epidemiologia , COVID-19/virologia , Células Cultivadas , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/fisiologia , Linfócitos T/virologia
6.
Nature ; 596(7870): 119-125, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34290406

RESUMO

Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1-3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma/imunologia , Especificidade por Substrato/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Humanos , Linfócitos do Interstício Tumoral/imunologia , Melanoma/sangue , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Transcriptoma/genética , Microambiente Tumoral
8.
Nat Methods ; 18(8): 881-892, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34282327

RESUMO

T cells express T cell receptors (TCRs) composed of somatically recombined TCRα and TCRß chains, which mediate recognition of major histocompatibility complex (MHC)-antigen complexes and drive the antigen-specific adaptive immune response to pathogens and cancer. The TCR repertoire in each individual is highly diverse, which allows for recognition of a wide array of foreign antigens, but also presents a challenge in analyzing this response using conventional methods. Recent studies have developed high-throughput sequencing technologies to identify TCR sequences, analyze their antigen specificities using experimental and computational tools, and pair TCRs with transcriptional and epigenetic cell state phenotypes in single cells. In this Review, we highlight these technological advances and describe how they have been applied to discover fundamental insights into T cell-mediated immunity.


Assuntos
Antígenos/imunologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única/métodos , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Humanos
9.
Sci Rep ; 11(1): 14275, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253751

RESUMO

SARS-CoV-2 infection is characterized by a highly variable clinical course with patients experiencing asymptomatic infection all the way to requiring critical care support. This variation in clinical course has led physicians and scientists to study factors that may predispose certain individuals to more severe clinical presentations in hopes of either identifying these individuals early in their illness or improving their medical management. We sought to understand immunogenomic differences that may result in varied clinical outcomes through analysis of T-cell receptor sequencing (TCR-Seq) data in the open access ImmuneCODE database. We identified two cohorts within the database that had clinical outcomes data reflecting severity of illness and utilized DeepTCR, a multiple-instance deep learning repertoire classifier, to predict patients with severe SARS-CoV-2 infection from their repertoire sequencing. We demonstrate that patients with severe infection have repertoires with higher T-cell responses associated with SARS-CoV-2 epitopes and identify the epitopes that result in these responses. Our results provide evidence that the highly variable clinical course seen in SARS-CoV-2 infection is associated to certain antigen-specific responses.


Assuntos
COVID-19/imunologia , Epitopos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/imunologia , Infecções Assintomáticas/epidemiologia , COVID-19/patologia , COVID-19/virologia , Aprendizado Profundo , Humanos , Receptores de Antígenos de Linfócitos T/genética , SARS-CoV-2/patogenicidade , Linfócitos T/imunologia , Linfócitos T/virologia
10.
Nat Commun ; 12(1): 3872, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162836

RESUMO

The tyrosine phosphatase CD45 is a major gatekeeper for restraining T cell activation. Its exclusion from the immunological synapse (IS) is crucial for T cell receptor (TCR) signal transduction. Here, we use expansion super-resolution microscopy to reveal that CD45 is mostly pre-excluded from the tips of microvilli (MV) on primary T cells prior to antigen encounter. This pre-exclusion is diminished by depleting cholesterol or by engineering the transmembrane domain of CD45 to increase its membrane integration length, but is independent of the CD45 extracellular domain. We further show that brief MV-mediated contacts can induce Ca2+ influx in mouse antigen-specific T cells engaged by antigen-pulsed antigen presenting cells (APC). We propose that the scarcity of CD45 phosphatase activity at the tips of MV enables or facilitates TCR triggering from brief T cell-APC contacts before formation of a stable IS, and that these MV-mediated contacts represent the earliest step in the initiation of a T cell adaptive immune response.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos Comuns de Leucócito/imunologia , Microvilosidades/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Células Cultivadas , Feminino , Células HEK293 , Humanos , Células Jurkat , Antígenos Comuns de Leucócito/genética , Antígenos Comuns de Leucócito/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microvilosidades/metabolismo , Fosforilação/imunologia , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/imunologia , Proteínas Tirosina Fosfatases/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismo
11.
Sci Rep ; 11(1): 13164, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162945

RESUMO

The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing CD4 and CD8 T-cell immunity to SARS-CoV-2 antigen. The T-cell reactivity to the predicted epitopes was higher than the Spike-S1 and S2 peptide pools in the unexposed donors. A key finding of our study is that pre-existing T-cell immunity to SARS-CoV-2 is contributed by TCRs that recognize common viral antigens such as Influenza and CMV, even though the viral epitopes lack sequence identity to the SARS-CoV-2 epitopes. This finding is in contrast to multiple published studies in which pre-existing T-cell immunity is suggested to arise from shared epitopes between SARS-CoV-2 and other common cold-causing coronaviruses. However, our findings suggest that SARS-CoV-2 reactive T-cells are likely to be present in many individuals because of prior exposure to flu and CMV viruses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Epitopos de Linfócito T/imunologia , Epitopos Imunodominantes , Glicoproteína da Espícula de Coronavírus/imunologia , Algoritmos , Células Clonais , Expressão Gênica , Humanos , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2
12.
Eur J Immunol ; 51(8): 1992-2005, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34081326

RESUMO

The phenotype of infused cells is a major determinant of Adoptive T-cell therapy (ACT) efficacy. Yet, the difficulty in deciphering multiparametric cytometry data limited the fine characterization of cellular products. To allow the analysis of dynamic and complex flow cytometry samples, we developed cytoChain, a novel dataset mining tool and a new analytical workflow. CytoChain was challenged to compare state-of-the-art and innovative culture conditions to generate stem-like memory cells (TSCM ) suitable for ACT. Noticeably, the combination of IL-7/15 and superoxides scavenging sustained the emergence of a previously unidentified nonexhausted Fit-TSCM signature, overlooked by manual gating and endowed with superior expansion potential. CytoChain proficiently traced back this population in independent datasets, and in T-cell receptor engineered lymphocytes. CytoChain flexibility and function were then further validated on a published dataset from circulating T cells in COVID-19 patients. Collectively, our results support the use of cytoChain to identify novel, functionally critical immunophenotypes for ACT and patients immunomonitoring.


Assuntos
Mineração de Dados/métodos , Citometria de Fluxo/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , COVID-19/sangue , COVID-19/imunologia , Citocinas/metabolismo , Engenharia Genética , Humanos , Memória Imunológica , Imunofenotipagem , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , SARS-CoV-2/imunologia
13.
Int J Mol Sci ; 22(11)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072732

RESUMO

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor-patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Técnicas de Cultura de Células , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Engenharia Genética , Humanos , Células Matadoras Naturais/metabolismo , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Resultado do Tratamento
14.
Nat Immunol ; 22(7): 809-819, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34140679

RESUMO

CD8+ T cells are critical mediators of cytotoxic effector function in infection, cancer and autoimmunity. In cancer and chronic viral infection, CD8+ T cells undergo a progressive loss of cytokine production and cytotoxicity, a state termed T cell exhaustion. In autoimmunity, autoreactive CD8+ T cells retain the capacity to effectively mediate the destruction of host tissues. Although the clinical outcome differs in each context, CD8+ T cells are chronically exposed to antigen in all three. These chronically stimulated CD8+ T cells share some common phenotypic features, as well as transcriptional and epigenetic programming, across disease contexts. A better understanding of these CD8+ T cell states may reveal novel strategies to augment clearance of chronic viral infection and cancer and to mitigate self-reactivity leading to tissue damage in autoimmunity.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Linfócitos T CD8-Positivos/imunologia , Doenças Transmissíveis/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Doença Crônica , Doenças Transmissíveis/genética , Doenças Transmissíveis/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Epigênese Genética , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais
15.
Curr Hematol Malig Rep ; 16(2): 218-233, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33939108

RESUMO

PURPOSE OF REVIEW: Both chimeric antigen receptor (CAR) T cells and T cell-engaging antibodies (BiAb) have been approved for the treatment of hematological malignancies. However, despite targeting the same antigen, they represent very different classes of therapeutics, each with its distinct advantages and drawbacks. In this review, we compare BiAb and CAR T cells with regard to their mechanism of action, manufacturing, and clinical application. In addition, we present novel strategies to overcome limitations of either approach and to combine the best of both worlds. RECENT FINDINGS: By now there are multiple approaches combining the advantages of BiAb and CAR T cells. A major area of research is the application of both formats for solid tumor entities. This includes improving the infiltration of T cells into the tumor, counteracting immunosuppression in the tumor microenvironment, targeting antigen heterogeneity, and limiting off-tumor on-target effects. BiAb come with the major advantage of being an off-the-shelf product and are more controllable because of their half-life. They have also been reported to induce less frequent and less severe adverse events. CAR T cells in turn demonstrate superior response rates, have the potential for long-term persistence, and can be additionally genetically modified to overcome some of their limitations, e.g., to make them more controllable.


Assuntos
Anticorpos Biespecíficos/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Anticorpos Biespecíficos/genética , Antígenos de Neoplasias/imunologia , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/etiologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
J Biol Chem ; 296: 100745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33957119

RESUMO

Fifty years ago, the first landmark structures of antibodies heralded the dawn of structural immunology. Momentum then started to build toward understanding how antibodies could recognize the vast universe of potential antigens and how antibody-combining sites could be tailored to engage antigens with high specificity and affinity through recombination of germline genes (V, D, J) and somatic mutation. Equivalent groundbreaking structures in the cellular immune system appeared some 15 to 20 years later and illustrated how processed protein antigens in the form of peptides are presented by MHC molecules to T cell receptors. Structures of antigen receptors in the innate immune system then explained their inherent specificity for particular microbial antigens including lipids, carbohydrates, nucleic acids, small molecules, and specific proteins. These two sides of the immune system act immediately (innate) to particular microbial antigens or evolve (adaptive) to attain high specificity and affinity to a much wider range of antigens. We also include examples of other key receptors in the immune system (cytokine receptors) that regulate immunity and inflammation. Furthermore, these antigen receptors use a limited set of protein folds to accomplish their various immunological roles. The other main players are the antigens themselves. We focus on surface glycoproteins in enveloped viruses including SARS-CoV-2 that enable entry and egress into host cells and are targets for the antibody response. This review covers what we have learned over the past half century about the structural basis of the immune response to microbial pathogens and how that information can be utilized to design vaccines and therapeutics.


Assuntos
Imunidade Adaptativa , Anticorpos Antivirais/química , Antígenos Virais/química , Imunidade Inata , Receptores de Antígenos de Linfócitos T/química , Receptores de Citocinas/química , SARS-CoV-2/imunologia , Alergia e Imunologia/história , Animais , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Apresentação do Antígeno , Antígenos Virais/genética , Antígenos Virais/imunologia , COVID-19/imunologia , COVID-19/virologia , Cristalografia/história , Cristalografia/métodos , História do Século XX , História do Século XXI , Humanos , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Citocinas/genética , Receptores de Citocinas/imunologia , SARS-CoV-2/patogenicidade , Recombinação V(D)J
17.
Nat Med ; 27(5): 820-832, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33958794

RESUMO

Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n = 29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n = 11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8+ T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4+ T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1+), specific macrophage phenotypes (CCR2+ or MMP9+) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7+, GZMK+) or inhibitory macrophages (CX3CR1+, C3+) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Análise de Célula Única/métodos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células Dendríticas/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Macrófagos/imunologia , Terapia Neoadjuvante/métodos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia
19.
Nat Rev Drug Discov ; 20(7): 531-550, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33972771

RESUMO

The adoptive transfer of T cells that are engineered to express chimeric antigen receptors (CARs) has shown remarkable success in treating B cell malignancies but only limited efficacy against other cancer types, especially solid tumours. Compared with haematological diseases, solid tumours present a unique set of challenges, including a lack of robustly expressed, tumour-exclusive antigen targets as well as highly immunosuppressive and metabolically challenging tumour microenvironments that limit treatment safety and efficacy. Here, we review protein- and cell-engineering strategies that seek to overcome these obstacles and produce next-generation T cells with enhanced tumour specificity and sustained effector function for the treatment of solid malignancies.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Engenharia de Proteínas , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética
20.
Immunity ; 54(6): 1245-1256.e5, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34004140

RESUMO

We examined how baseline CD4+ T cell repertoire and precursor states impact responses to pathogen infection in humans using primary immunization with yellow fever virus (YFV) vaccine. YFV-specific T cells in unexposed individuals were identified by peptide-MHC tetramer staining and tracked pre- and post-vaccination by tetramers and TCR sequencing. A substantial number of YFV-reactive T cells expressed memory phenotype markers and contained expanded clones in the absence of exposure to YFV. After vaccination, pre-existing YFV-specific T cell populations with low clonal diversity underwent limited expansion, but rare populations with a reservoir of unexpanded TCRs generated robust responses. These altered dynamics reorganized the immunodominance hierarchy and resulted in an overall increase in higher avidity T cells. Thus, instead of further increasing the representation of dominant clones, YFV vaccination recruits rare and more responsive T cells. Our findings illustrate the impact of vaccines in prioritizing T cell responses and reveal repertoire reorganization as a key component of effective vaccination.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Vacina contra Febre Amarela/imunologia , Febre Amarela/imunologia , Vírus da Febre Amarela/imunologia , Adulto , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/imunologia , Células Cultivadas , Chlorocebus aethiops , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Vacinação/métodos , Células Vero , Febre Amarela/virologia
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