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1.
Adv Exp Med Biol ; 1255: 29-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949388

RESUMO

T cells recognize peptides bound to major histocompatibility complex (MHC) class I and class II molecules at the cell surface. This recognition is accomplished by the expression of T cell receptors (TCR) which are required to be diverse and adaptable in order to accommodate the various and vast number of antigens presented on the MHCs. Thus, determining TCR repertoires of effector T cells is necessary to understand the immunological process in responding to cancer progression, infection, and autoimmune development. Furthermore, understanding the TCR repertoires will provide a solid framework to predict and test the antigen which is more critical in autoimmunity. However, it has been a technical challenge to sequence the TCRs and provide a conceptual context in correlation to the vast number of TCR repertoires in the immunological system. The exploding field of single-cell sequencing has changed how the repertoires are being investigated and analyzed. In this review, we focus on the biology of TCRs, TCR signaling and its implication in autoimmunity. We discuss important methods in bulk sequencing of many cells. Lastly, we explore the most pertinent platforms in single-cell sequencing and its application in autoimmunity.


Assuntos
Receptores de Antígenos de Linfócitos T/genética , Análise de Sequência , Análise de Célula Única , Animais , Autoimunidade/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
3.
Nat Commun ; 11(1): 4454, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901001

RESUMO

Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/virologia , Doença Crônica , Citotoxicidade Imunológica , Modelos Animais de Doenças , Regulação para Baixo , Tolerância Imunológica , Imunidade Celular , Técnicas In Vitro , Ativação Linfocitária , Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Transdução de Sinais/imunologia
4.
Nature ; 585(7824): 277-282, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32879489

RESUMO

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours1-4, but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8+ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach.


Assuntos
Sistema L de Transporte de Aminoácidos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Histonas/metabolismo , Metionina/metabolismo , Metilação , Neoplasias/metabolismo , Sistema L de Transporte de Aminoácidos/deficiência , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Epigênese Genética , Feminino , Histonas/química , Humanos , Camundongos , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT5/metabolismo
5.
Front Immunol ; 11: 1870, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983106

RESUMO

Coronavirus disease 2019 (COVID-19) which is caused by the novel SARS-CoV-2 virus is a severe flu-like illness which is associated with hyperinflammation and immune dysfunction. The virus induces a strong T and B cell response but little is known about the immune pathology of this viral infection. Acute Plasmodium falciparum malaria also causes acute clinical illness and is characterized by hyperinflammation due to the strong production of pro-inflammatory cytokines and a massive activation of T cells. In malaria, T cells express a variety of co-inhibitory receptors which might be a consequence of their activation but also might limit their overwhelming function. Thus, T cells are implicated in protection as well as in pathology. The outcome of malaria is thought to be a consequence of the balance between co-activation and co-inhibition of T cells. Following the hypothesis that T cells in COVID-19 might have a similar, dual function, we comprehensively characterized the differentiation (CCR7, CD45RO) and activation status (HLA-DR, CD38, CD69, CD226), the co-expression of co-inhibitory molecules (PD1, TIM-3, LAG-3, BTLA, TIGIT), as well as the expression pattern of the transcription factors T-bet and eomes of CD8+ and CD4+ T cells of PBMC of n = 20 SARS-CoV-2 patients compared to n = 10 P. falciparum infected patients and n = 13 healthy controls. Overall, acute COVID-19 and malaria infection resulted in a comparably elevated activation and altered differentiation status of the CD8+ and CD4+ T cell populations. T effector cells of COVID-19 and malaria patients showed higher frequencies of the inhibitory receptors T-cell immunoglobulin mucin-3 (TIM-3) and Lymphocyte-activation gene-3 (LAG-3) which was linked to increased activation levels and an upregulation of the transcription factors T-bet and eomes. COVID-19 patients with a more severe disease course showed higher levels of LAG-3 and TIM-3 than patients with a mild disease course. During recovery, a rapid normalization of these inhibitory receptors could be observed. In summary, comparing the expression of different co-inhibitory molecules in CD8+ and CD4+ T cells in COVID-19 vs. malaria, there is a transient increase of the expression of certain inhibitory receptors like LAG-3 and TIM-3 in COVID-19 in the overall context of acute immune activation.


Assuntos
Antígenos CD/metabolismo , Betacoronavirus/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/imunologia , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Ativação Linfocitária/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/isolamento & purificação , Pneumonia Viral/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Doença Aguda , Adulto , Idoso , Células Cultivadas , Estudos de Coortes , Infecções por Coronavirus/virologia , Feminino , Humanos , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/metabolismo , Índice de Gravidade de Doença
6.
Nat Commun ; 11(1): 4414, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32887877

RESUMO

CD4+ helper T cells contribute important functions to the immune response during pathogen infection and tumor formation by recognizing antigenic peptides presented by class II major histocompatibility complexes (MHC-II). While many computational algorithms for predicting peptide binding to MHC-II proteins have been reported, their performance varies greatly. Here we present a yeast-display-based platform that allows the identification of over an order of magnitude more unique MHC-II binders than comparable approaches. These peptides contain previously identified motifs, but also reveal new motifs that are validated by in vitro binding assays. Training of prediction algorithms with yeast-display library data improves the prediction of peptide-binding affinity and the identification of pathogen-associated and tumor-associated peptides. In summary, our yeast-display-based platform yields high-quality MHC-II-binding peptide datasets that can be used to improve the accuracy of MHC-II binding prediction algorithms, and potentially enhance our understanding of CD4+ T cell recognition.


Assuntos
Epitopos de Linfócito T/genética , Oligopeptídeos , Sítios de Ligação , Linfócitos T CD4-Positivos/imunologia , Técnicas de Visualização da Superfície Celular , Bases de Dados de Proteínas , Epitopos de Linfócito T/química , Epitopos de Linfócito T/metabolismo , Genes MHC da Classe II , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Oligopeptídeos/química , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Ligação Proteica/genética , Receptores de Antígenos de Linfócitos T , Proteínas Recombinantes/metabolismo , Saccharomyces cerevisiae/metabolismo
7.
Signal Transduct Target Ther ; 5(1): 156, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796814

RESUMO

The global Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has affected more than eight million people. There is an urgent need to investigate how the adaptive immunity is established in COVID-19 patients. In this study, we profiled adaptive immune cells of PBMCs from recovered COVID-19 patients with varying disease severity using single-cell RNA and TCR/BCR V(D)J sequencing. The sequencing data revealed SARS-CoV-2-specific shuffling of adaptive immune repertories and COVID-19-induced remodeling of peripheral lymphocytes. Characterization of variations in the peripheral T and B cells from the COVID-19 patients revealed a positive correlation of humoral immune response and T-cell immune memory with disease severity. Sequencing and functional data revealed SARS-CoV-2-specific T-cell immune memory in the convalescent COVID-19 patients. Furthermore, we also identified novel antigens that are responsive in the convalescent patients. Altogether, our study reveals adaptive immune repertories underlying pathogenesis and recovery in severe versus mild COVID-19 patients, providing valuable information for potential vaccine and therapeutic development against SARS-CoV-2 infection.


Assuntos
Linfócitos B/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Imunidade Celular , Imunidade Humoral , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Linfócitos B/classificação , Linfócitos B/virologia , Betacoronavirus/imunologia , Estudos de Casos e Controles , China , Convalescença , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Progressão da Doença , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/imunologia , Humanos , Memória Imunológica , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Receptores de Antígenos de Linfócitos B/classificação , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos T/classificação , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Índice de Gravidade de Doença , Análise de Célula Única , Linfócitos T/classificação , Linfócitos T/virologia
8.
Nat Commun ; 11(1): 4166, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820173

RESUMO

T cells engineered to express chimeric antigen receptors (CAR-T cells) have shown impressive clinical efficacy in the treatment of B cell malignancies. However, the development of CAR-T cell therapies for solid tumors is hampered by the lack of truly tumor-specific antigens and poor control over T cell activity. Here we present an avidity-controlled CAR (AvidCAR) platform with inducible and logic control functions. The key is the combination of (i) an improved CAR design which enables controlled CAR dimerization and (ii) a significant reduction of antigen-binding affinities to introduce dependence on bivalent interaction, i.e. avidity. The potential and versatility of the AvidCAR platform is exemplified by designing ON-switch CARs, which can be regulated with a clinically applied drug, and AND-gate CARs specifically recognizing combinations of two antigens. Thus, we expect that AvidCARs will be a highly valuable platform for the development of controllable CAR therapies with improved tumor specificity.


Assuntos
Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo
9.
BMC Bioinformatics ; 21(1): 314, 2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32677886

RESUMO

BACKGROUND: Recent advances in DNA sequencing technologies have enabled significant leaps in capacity to generate large volumes of DNA sequence data, which has spurred a rapid growth in the use of bioinformatics as a means of interrogating antibody variable gene repertoires. Common tools used for annotation of antibody sequences are often limited in functionality, modularity and usability. RESULTS: We have developed PyIR, a Python wrapper and library for IgBLAST, which offers a minimal setup CLI and API, FASTQ support, file chunking for large sequence files, JSON and Python dictionary output, and built-in sequence filtering. CONCLUSIONS: PyIR offers improved processing speed over multithreaded IgBLAST (version 1.14) when spawning more than 16 processes on a single computer system. Its customizable filtering and data encapsulation allow it to be adapted to a wide range of computing environments. The API allows for IgBLAST to be used in customized bioinformatics workflows.


Assuntos
Imunoglobulinas/genética , Receptores de Antígenos de Linfócitos T/genética , Alinhamento de Sequência , Software , Sequência de Bases , Humanos , Análise de Sequência de DNA , Fatores de Tempo , Interface Usuário-Computador
10.
Proc Natl Acad Sci U S A ; 117(32): 19388-19398, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727906

RESUMO

CD8+ T cells play pivotal roles in eradicating pathogens and tumor cells. T cell receptor (TCR) signaling is vital for the optimal activation of CD8+ T cells. Upon TCR engagement, the transmembrane adapter protein LAT (linker for activation of T cells) recruits other key signaling molecules and forms the "LAT signalosome" for downstream signal transduction. However, little is known about which functional partners could restrain the formation of the LAT signalosome and inhibit CD8+ cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Here we have demonstrated that LRCH1 (leucine-rich repeats and calponin homology domain containing 1) directly binds LAT, reduces LAT phosphorylation and interaction with GRB2, and also promotes the endocytosis of LAT. Lrch1 -/- mice display better protection against influenza virus and Listeria infection, with enhanced CD8+ T cell proliferation and cytotoxicity. Adoptive transfer of Lrch1 -/- CD8+ CTLs leads to increased B16-MO5 tumor clearance in vivo. Furthermore, knockout of LRCH1 in human chimeric antigen receptor (CAR) T cells that recognize the liver tumor-associated antigen glypican-3 could improve CAR T cell migration and proliferation in vitro. These findings suggest LRCH1 as a potential translational target to improve T cell immunotherapy against infection and tumors.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linfócitos T CD8-Positivos/imunologia , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/deficiência , Transdução de Sinais , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Movimento Celular , Células Cultivadas , Citotoxicidade Imunológica , Endocitose , Proteína Adaptadora GRB2/metabolismo , Humanos , Imunoterapia Adotiva , Infecções/imunologia , Infecções/microbiologia , Infecções/virologia , Interferon gama/metabolismo , Neoplasias Pulmonares/terapia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Fosforilação , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/metabolismo
11.
Zhonghua Xue Ye Xue Za Zhi ; 41(6): 490-494, 2020 Jun 14.
Artigo em Chinês | MEDLINE | ID: mdl-32654463

RESUMO

Objective: This study aimed to examine the safety and efficacy of CD19 chimeric antigen receptor T cell (CD19 CAR-T) therapy in relapsed/refractory Philadelphia chromosome-positive acute B-precursor lymphoblastic leukemia (R/R Ph(+) B-ALL) . Methods: The clinical data of 14 patients with R/R Ph(+) B-ALL treated with CD19 CAR-T cell therapy from November 2016 to April 2019 were retrospectively analyzed. Results: Among the 14 patients in this study, 7 were male and 7 were female, with a median age of 33 (7-66) years old. The efficacy was evaluated on the 28th day following CAR-T cells infusion; the overall response rate was 100.0% (14/14) , the complete response (CR) rate was 92.9% (13/14) , and the partial response (PR) rate was 7.1% (1/14) . After CAR-T cells infusion,12 cases (85.7%) developed cytokine release syndrome (CRS) : 1 case of grade 1 CRS, 4 cases of grade 2 CRS, 6 cases of grade 3 CRS, and 1 case of grade 4 CRS. Moreover, one case developed CAR T-cell-related encephalopathy syndrome (CRES) ; 14 cases had Ⅲ-Ⅳ hematological toxicity; and 13 CR cases had B cell dysplasia. These adverse reactions were all controllable. The median follow-up time was 441 (182-923) d. The median overall survival (OS) and progression-free survival (PFS) were 515 [95% confidence interval (CI) 287-743] days and 207 (95% CI 123-301) days, respectively. Conclusion: CD19 CAR-T cell therapy is safe and effective for R/R Ph(+) B-ALL treatment. However, the long-term efficacy needs to be further improved.


Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Adulto , Idoso , Antígenos CD19 , Criança , Feminino , Humanos , Imunoterapia Adotiva , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T , Estudos Retrospectivos , Linfócitos T , Adulto Jovem
12.
Nat Commun ; 11(1): 3755, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709874

RESUMO

Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders.


Assuntos
Disbiose/imunologia , Inflamação/patologia , Intestinos/patologia , Células T Invariáveis Associadas à Mucosa/patologia , Obesidade/metabolismo , Tecido Adiposo/patologia , Animais , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica , Disbiose/complicações , Microbioma Gastrointestinal , Teste de Tolerância a Glucose , Íleo/patologia , Inflamação/complicações , Mucosa Intestinal/patologia , Intestinos/diagnóstico por imagem , Ligantes , Contagem de Linfócitos , Macrófagos/metabolismo , Imagem por Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/complicações , Obesidade/diagnóstico por imagem , Fenótipo , Pterinas/farmacologia , Receptores de Antígenos de Linfócitos T/metabolismo
13.
Proc Natl Acad Sci U S A ; 117(29): 17156-17165, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611812

RESUMO

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.


Assuntos
Diferenciação Celular , Tolerância Imunológica , Células T Matadoras Naturais , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T , Timócitos
14.
Curr Res Transl Med ; 68(3): 111-118, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32620465

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly across the world. Currently, the COVID-19 pandemic is affecting the continuity of essential routine healthcare services and procedures, including chimeric antigen receptor T-cell (CAR-T) therapy, a life-saving option for patients with relapsed/refractory (R/R) hematologic malignancies. Due to the rapid disease progression of hematological malignancies, there is an urgent need to manufacture and utilize CAR T-cells. However, CAR-T treatment has become extraordinarily challenging during this COVID-19 pandemic. Thus, many medical and technical factors must now be taken into consideration before, during, and after CAR-T therapy. The purpose of this review is to provide brief suggestions for rational decision-making strategies in evaluating and selecting CAR T-cell treatment and appropriate CAR T-cell products, and protective strategies for medical staff and patients to prevent infection in the midst of the current COVID-19 pandemic.


Assuntos
Infecções por Coronavirus/prevenção & controle , Assistência à Saúde/organização & administração , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Controle de Infecções/organização & administração , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Receptores de Antígenos de Linfócitos T/imunologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/epidemiologia , Assistência à Saúde/métodos , Assistência à Saúde/normas , Assistência à Saúde/tendências , Neoplasias Hematológicas/epidemiologia , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Controle de Infecções/métodos , Controle de Infecções/normas , Controle de Infecções/tendências , Pneumonia Viral/epidemiologia , Serviços Preventivos de Saúde/métodos , Serviços Preventivos de Saúde/organização & administração , Serviços Preventivos de Saúde/normas , Serviços Preventivos de Saúde/tendências
15.
Mol Immunol ; 125: 43-50, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32645549

RESUMO

The CD8 T cell response to the HLA-A2-restricted epitope LLWNGPMAV (LLW) of the non-structural protein 4b of Yellow Fever Virus (YFV) is remarkably immunodominant, highly prevalent and powerful in YFV-vaccinated humans. Here we used a combinatorial peptide library screening in the context of an A2/LLW-specific CD8 T cell clone to identify a superagonist that features a methionine to isoleucine substitution at position 7. Based on in silico modeling, the functional enhancement of this LLW-7I mutation was associated with alterations in the structural dynamics of the peptide in the major histocompatibility complex (pMHC) binding with the T cell receptor (TCR). While the TCR off-rate of LLW-7I pMHC is comparable to the wild type peptide, the rigidity of the 7I peptide seems to confer less entropy loss upon TCR binding. This LLW-7I superagonist is an example of improved functionality in human CD8 T cells associated with optimized ligand rigidity for TCR binding and not with changes in TCR:pMHC off-rate kinetics.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epitopos Imunodominantes/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas não Estruturais Virais/imunologia , Vírus da Febre Amarela/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Antígeno HLA-A2/química , Antígeno HLA-A2/imunologia , Humanos , Epitopos Imunodominantes/química , Modelos Moleculares , Mutação , Biblioteca de Peptídeos , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T/química
16.
Scand J Immunol ; 92(4): e12927, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32640053

RESUMO

Malignant melanoma has seen monumental changes in treatment options the last decade from the very poor results of dacarbazine treatment to the modern-day use of targeted therapies and immune checkpoint inhibitors. Melanoma has a high mutational burden making it more capable of evoking immune responses than many other tumours. Even when considering double immune checkpoint blockade with anti-CTLA-4 and anti-PD-1, we still have far to go in melanoma treatment as 50% of patients with metastatic disease do not respond to current treatment. Alternative immunotherapy should therefore be considered. Since melanoma has a high mutational burden, it is considered more immunogenic than many other tumours. T cell receptor (TCR) therapy could be a possible way forward, either alone or in combination, to improve the response rates of this deadly disease. Melanoma is one of the cancers where TCR therapy has been frequently applied. However, the number of antigens targeted remains fairly limited, although advanced personalized therapies aim at also targeting private mutations. In this review, we look at possible aspects of targeting TCR therapy towards melanoma and provide an implication of its use in the future.


Assuntos
Imunoterapia/métodos , Melanoma/imunologia , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/terapia , Animais , Humanos
17.
Nat Commun ; 11(1): 3187, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32581235

RESUMO

The application of adoptive T cell therapies, including those using chimeric antigen receptor (CAR)-modified T cells, to solid tumors requires combinatorial strategies to overcome immune suppression associated with the tumor microenvironment. Here we test whether the inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment may help to recruit and potentiate the functionality of CAR T cells. Contrary to our hypothesis, VSVmIFNß infection is associated with attrition of murine EGFRvIII CAR T cells in a B16EGFRvIII model, despite inducing a robust proinflammatory shift in the chemokine profile. Mechanistically, type I interferon (IFN) expressed following infection promotes apoptosis, activation, and inhibitory receptor expression, and interferon-insensitive CAR T cells enable combinatorial therapy with VSVmIFNß. Our study uncovers an unexpected mechanism of therapeutic interference, and prompts further investigation into the interaction between CAR T cells and oncolytic viruses to optimize combination therapy.


Assuntos
Imunoterapia Adotiva , Interferon beta/metabolismo , Vírus Oncolíticos/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Terapia Combinada , Feminino , Interferon beta/genética , Ativação Linfocitária , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Terapia Viral Oncolítica , Vírus Oncolíticos/genética , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Baço/imunologia
20.
Trends Pharmacol Sci ; 41(8): 518-530, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32576386

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected several millions and killed more than quarter of a million worldwide to date. Important questions have remained unanswered: why some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection. Here, we discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of the disease, COVID-19. We highlight the scientific rationale for comprehensive and longitudinal TCR analyses in COVID-19 and reason that analyzing TCR repertoire in COVID-19 patients would reveal important findings that may explain the outcome disparity observed in these patients. Finally, we provide a framework describing the different strategies, the advantages, and the challenges involved in obtaining useful TCR repertoire data to advance our fight against COVID-19.


Assuntos
Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Humanos , Pandemias , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Linfócitos T/imunologia
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