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1.
PLoS Biol ; 18(3): e3000648, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32182234

RESUMO

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.


Assuntos
Apoptose/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Proteínas com Domínio T/imunologia , Animais , Variação Antigênica/imunologia , Sobrevivência Celular/imunologia , Células Cultivadas , Seleção Clonal Mediada por Antígeno/genética , Seleção Clonal Mediada por Antígeno/imunologia , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária , Camundongos , Células Precursoras de Linfócitos T/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Proteínas com Domínio T/genética
2.
Nat Commun ; 11(1): 821, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041953

RESUMO

The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (TSCM) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that TSCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/ß-catenin signature in CD4 TSCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/ß-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 TSCM. Our data thus hint that reversing TSCM defects by metabolic targeting of the Wnt/ß-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Precursoras de Linfócitos T/imunologia , Via de Sinalização Wnt/imunologia , Envelhecimento/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Perfilação da Expressão Gênica , Infecções por HIV/imunologia , Humanos , Memória Imunológica , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Timo/imunologia , Via de Sinalização Wnt/genética , beta Catenina/imunologia
3.
PLoS Biol ; 18(2): e3000590, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32069316

RESUMO

DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença/genética , Antígenos de Histocompatibilidade Classe II/genética , Animais , Células Apresentadoras de Antígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade/genética , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Colágeno/administração & dosagem , Colágeno/imunologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Glicoproteína Mielina-Oligodendrócito/imunologia , Peptídeos/imunologia , Células Precursoras de Linfócitos T/imunologia , Timo/imunologia
4.
Nat Rev Immunol ; 20(2): 128-136, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31591533

RESUMO

Cytotoxic T cell immunity in response to chronic infections and tumours is maintained by a specialized population of CD8+ T cells that exhibit hallmarks of both exhausted and memory cells and give rise to terminally differentiated exhausted effector cells that contribute to viral or tumour control. Importantly, recent work suggests these cells, which we refer to as 'precursor exhausted' T (TPEX) cells, are responsible for the proliferative burst that generates effector T cells in response to immune checkpoint blockade targeting programmed cell death 1 (PD1), and increased TPEX cell frequencies have recently been linked to increased patient survival. We believe the recent discovery of TPEX cells not only represents a paradigm shift in our understanding of the mechanisms that maintain CD8+ T cell responses in chronic infections and tumours but also opens up unexpected avenues for the development of new and innovative therapeutic approaches. In this Opinion article, we discuss the differentiation and function of TPEX cells and suggest that targeting these cells may be key for successful immunotherapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Neoplasias/tratamento farmacológico , Células Precursoras de Linfócitos T/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Subpopulações de Linfócitos T/imunologia , Diferenciação Celular , Humanos , Memória Imunológica , Neoplasias/imunologia
5.
Nat Immunol ; 20(11): 1456-1468, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636466

RESUMO

T cell specification and commitment require Notch signaling. Although the requirement for Notch signaling during intrathymic T cell development is known, it is still unclear whether the onset of T cell priming can occur in a prethymic niche and whether RBPJ-dependent Notch signaling has a role during this event. Here, we established an Rbpj-inducible system that allowed temporal and tissue-specific control of the responsiveness to Notch in all hematopoietic cells. Using this system, we found that Notch signaling was required before the early T cell progenitor stage in the thymus. Lymphoid-primed multipotent progenitors in the bone marrow underwent Notch signaling with Rbpj induction, which inhibited development towards the myeloid lineage in thymus-seeding progenitors. Thus, our results indicated that the onset of T cell differentiation occurred in a prethymic setting, and that Notch played an important role during this event.


Assuntos
Diferenciação Celular/imunologia , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Células Precursoras de Linfócitos T/fisiologia , Receptores Notch/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Linhagem da Célula/imunologia , Separação Celular , Feminino , Citometria de Fluxo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Masculino , Camundongos , Camundongos Transgênicos , Cultura Primária de Células , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/metabolismo , Timo/citologia , Timo/imunologia
6.
Immunity ; 51(5): 930-948.e6, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31604687

RESUMO

Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.


Assuntos
Diferenciação Celular/genética , Linfopoese/genética , Organogênese/genética , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/metabolismo , Timo/embriologia , Biomarcadores , Diferenciação Celular/imunologia , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Linfopoese/imunologia , Detecção de Sinal Psicológico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismo , Transcriptoma
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 673-684, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204916

RESUMO

OBJECTIVE: To identify the differentially expressed gene (DEG) core genes in early T-cell precursor acute lymphoblastic leukemia (ETP ALL) and to analyze their interactions with upstream miRNAs, lncRNAs and involved pathways; to clarify the regulatory mechanism of ETP ALL development; and to explore the molecular targets for clinical diagnosis and treatment. METHODS: The DEG of ETP ALL were screened based on the intersection of GEO database and TCGA database. The functional enrichment analysis and interaction analysis were carried out for DEG. Next, MCODE algorithm was used to screen core genes of DEG, and the mirDIP online tool and starBase online tool were utilized to predict upstream miRNA and lncRNA of the core genes. RESULTS: A total of 424 DEG with a high credibility were identified, which were mainly enriched in the biological activity, such as transcriptional regulation, signaling pathway and protein function activation according to GO function, and the KEGG pathway was enriched in hematopoiesis, anoxic stress response, transcriptional misregulation, immunity and other functions, which interrelated each other 7 core genes were identified. Subsequently, 7 miRNAs and 19 lncRNAs were predicted to meet screening criteria. Finally, a lncRNA-miRNA-mRNA-pathway regulatory network was constructed. CONCLUSION: The DEG in ETP ALL has been identified based on data mining methods; the core genes have been gained by co-expression analysis, and their upstream miRNA and lncRNA can be predicted for the early diagnosis of ETP ALL, thus providing a theoretical basis for the early diagnosis and reasonable treatment of ETP ALL, and helping to look for new tumor biomarkers of ETP ALL different from classical T-ALL.


Assuntos
Células Precursoras de Linfócitos T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , MicroRNAs , RNA Longo não Codificante , RNA Mensageiro
8.
J Exp Med ; 216(4): 884-899, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30898894

RESUMO

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still arise from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells. Thymus-derived lung ILC2s of E protein-deficient mice show different transcriptomes, proliferative properties, and cytokine responses from wild-type counterparts, suggesting potentially distinct functions.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Células Precursoras de Linfócitos T/metabolismo , Fator de Transcrição 4/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular , Interleucina-4/metabolismo , Pulmão/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Timo/citologia , Fator de Transcrição 4/genética , Transcrição Genética , Transcriptoma
9.
Scand J Immunol ; 89(3): e12739, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30506564

RESUMO

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by autoantibody-mediated platelet destruction. Multiple factors have been implicated in ITP pathogenesis, including T-lymphocyte dysfunctions. Increasing studies have indicated that stem cell memory-like T cell (TSCM) plays an important role in the development of multiple autoimmune diseases. This study aimed to explore the clinical correlation between the TSCM subset and ITP. The percentages of peripheral blood naïve T cells (TNs), TSCMs, central memory T cells (TCMs), effector memory T cells (TEMs) and effector T cells (TEs) among CD4+ and CD8+ T cells in 20 ITP patients before and after treatment were detected using flow cytometry. Our results showed that the percentages of peripheral blood CD4+ and CD8+ T cells in ITP patients were imbalanced. The percentage of CD8+ TSCMs in peripheral blood before treatment in ITP patients was significantly higher than that in healthy controls, whereas the percentages of the other T cell subsets did not exhibit significant differences. Our study further analysed the correlation between the change in the percentage of CD8+ TSCMs and the treatment efficacy. The results showed that the percentage of peripheral blood CD8+ TSCMs in ITP patients after glucocorticoid treatment significantly decreased and the changes of the percentages of CD8+ TSCMs before and after treatment in complete response (CR) and response (R) patients were obvious. Our finding showed that the imbalance of the percentage of CD8+ TSCMs might be involved in the development of ITP and might serve as a novel indicator of efficacy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Células Precursoras de Linfócitos T/imunologia , Púrpura Trombocitopênica Idiopática/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Methods Mol Biol ; 1884: 87-117, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30465197

RESUMO

This chapter will describe the current methodologies to isolate and expand NK cells from Peripheral Blood (PB) or tissues for "in vitro" studies, including NK cell antitumor immune function. In addition, methods to induce NK cell maturation, differentiation, and expansion from CD34+ precursors will also be described. Finally, it will also be treated the topical issue of the characterization of new functionally and phenotypically defined NK cell subsets.


Assuntos
Separação Celular/métodos , Citometria de Fluxo/métodos , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos/imunologia , Neoplasias/imunologia , Antígenos CD34/metabolismo , Diferenciação Celular/imunologia , Separação Celular/instrumentação , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Sangue Fetal/citologia , Citometria de Fluxo/instrumentação , Corantes Fluorescentes/química , Humanos , Vigilância Imunológica , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/metabolismo , Células Precursoras de Linfócitos T/fisiologia , Cultura Primária de Células/instrumentação , Cultura Primária de Células/métodos
11.
Zhonghua Xue Ye Xue Za Zhi ; 40(12): 1021-1025, 2019 Dec 14.
Artigo em Chinês | MEDLINE | ID: mdl-32023734

RESUMO

Objective: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a recently recognized high-risk T lymphoblastic leukemia subgroup. The optimal therapeutic approaches to adult patients with ETP-ALL are poorly characterized. In this study, we explore the efficacy and outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for ETP-ALL. Methods: The clinical data of 23 patients with ETP-ALL receiving allo-HSCT from 2010 to 2018 were retrospectively analyzed. Patients with ETP-ALL were diagnosed based on the characteristic immunophenotypes. Second-generation sequencing was done in all patients. As to the donors, 12 patients had haploidentical donors (Haplo-HSCT) , 7 HLA-matched sibling donors (Sib-HSCT) and 4 HLA-matched unrelated donors (URD-HSCT) . Before transplantation, 19 patients achieved complete remission (CR) and 4 patients without. Results: The main clinical features of ETP-ALL included high white blood cell counts in 5 patients, splenomegaly in 14, lymphadenopathy in 19, and thymus masses in 5. According to cytogenetic and molecular characteristics, 11 patients had gene mutations related to myeloid tumors, and 7 with high risk Karyotype. After first induction regimen, 14/23 patients achieved CR. 5 patients reached CR after more than 2 cycles of chemotherapy, while another 4 patients did not reach CR. After allo-HSCT, 22 patients were successfully implanted. The median time of granulocyte and platelet reconstitution was +12 and +19 days. One patient died of transplant-related infection at +14 days. The estimated 18-month overall survival (OS) and relapse-free survival (RFS) rates were (55.0±14.4) % and (48.1±14.7) % respectively. Transplant-related mortality was 4.3%. The median OS in patients achieving CR before transplantation was 20 months, however, that in patients without CR was only 13 months. OS and RFS between haplo-HSCT and sib-HSCT were comparable (P=0.460 and 0.420 respectively) . Conclusions: Allo-HSCT is an effective therapy in some patients with ETP-ALL. Salvage HSCT cannot overcome the poor outcome. Haplo-HSCT and sib-HSCT in ETP-ALL patients have the similar clinical outcome.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Células Precursoras de Linfócitos T , Adulto , Humanos , Indução de Remissão , Estudos Retrospectivos
12.
Zhonghua Xue Ye Xue Za Zhi ; 40(7): 561-567, 2019 Jul 14.
Artigo em Chinês | MEDLINE | ID: mdl-32397018

RESUMO

Objective: To evaluate the clinical characteristics of T-cell acute leukemia/lymphoma (T-ALL) and explore the prognosis significance of early T-cell precursor leukemia/lymphoma. Methods: A cohort of 126 patients diagnosed with T-ALL from 2008 to 2014 in West China Hospital, Sichuan University were enrolled in this study. They were further categorized by immunophenotype according to the expression of T-cell lineage markers CD1a, CD8, CD5 and one or more stem cell or myeloid markers. The laboratory indicators and prognosis factors were also statistically analyzed. Results: Of all patients, the ratio of male to female was 2.5∶1, with the median age of 25 years old (range 14 to 77) . The percentage of ETP-ALL was up to 47.6%. T-ALL patients showed higher ratio in first clinical remission rate (CR(1)) than T-LBL ones (64.4% vs 30.8%, P=0.032) . Group with WBC count higher than 50×10(9)/L at presentation showed higher ration of achieving CR(1) than those lower than 50×10(9)/L (78.4% vs 50.9%, P=0.010) . In comparison with the non-ETP-ALL, ETP-ALL patients had older age of onset (P<0.001) , lower WBC count (P<0.001) , lower risk of CNS involvement (10.0% vs 30.2%, P=0.009) and slightly inferior overall survival (P=0.073) . T-cell lineage markers CD1a(-), CD8(-) and CD4(-) positive patients had higher CR(1) than their corresponding negative ones (P=0.002, P=0.000, P=0.001) , while CD33(-) and CD56(-) positive patients had lower ratio of achieving CR(1) than their negative ones, respectively (P=0.035, P=0.035) . Conclusion: Flow cytometry and associated markers for immunophenotyping was of significance in the diagnosis and prognosis monitoring of T-ALL/LBL. The percentage of ETP-ALL/LBL subtype was high in Chinese adolescent and adult T-ALL patients. ETP-ALL/LBL was a high risk subtype, which needs more precise standard for diagnosis and advanced therapies for better outcome.


Assuntos
Células Precursoras de Linfócitos T/citologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Adolescente , Adulto , Idoso , China , Feminino , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Prognóstico , Adulto Jovem
13.
Nat Immunol ; 19(12): 1427-1440, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30374131

RESUMO

Multipotent progenitor cells confirm their T cell-lineage identity in the CD4-CD8- double-negative (DN) pro-T cell DN2 stages, when expression of the essential transcription factor Bcl11b begins. In vivo and in vitro stage-specific deletions globally identified Bcl11b-controlled target genes in pro-T cells. Proteomics analysis revealed that Bcl11b associated with multiple cofactors and that its direct action was needed to recruit those cofactors to selective target sites. Regions near functionally regulated target genes showed enrichment for those sites of Bcl11b-dependent recruitment of cofactors, and deletion of individual cofactors relieved the repression of many genes normally repressed by Bcl11b. Runx1 collaborated with Bcl11b most frequently for both activation and repression. In parallel, Bcl11b indirectly regulated a subset of target genes by a gene network circuit via the transcription inhibitor Id2 (encoded by Id2) and transcription factor PLZF (encoded by Zbtb16); Id2 and Zbtb16 were directly repressed by Bcl11b, and Id2 and PLZF controlled distinct alternative programs. Thus, our study defines the molecular basis of direct and indirect Bcl11b actions that promote T cell identity and block alternative potentials.


Assuntos
Linfopoese/imunologia , Células Precursoras de Linfócitos T/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/biossíntese , Proteínas Repressoras/imunologia , Proteínas Supressoras de Tumor/imunologia , Animais , Diferenciação Celular/imunologia , Regulação da Expressão Gênica/imunologia , Proteína 2 Inibidora de Diferenciação/biossíntese , Proteína 2 Inibidora de Diferenciação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Precursoras de Linfócitos T/citologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia
14.
Eur J Immunol ; 48(9): 1573-1579, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29979809

RESUMO

Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m2 intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ∼30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ∼50%, including those with a distinctly mature CD19- phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity.


Assuntos
Autoanticorpos/sangue , Bortezomib/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Plasmócitos/efeitos dos fármacos , Células Precursoras de Linfócitos B/efeitos dos fármacos , Células Precursoras de Linfócitos T/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Inibidores de Proteassoma/uso terapêutico , Proteínas do Sistema Complemento/metabolismo , Humanos , Imunoglobulinas/sangue , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Contagem de Linfócitos , Plasmócitos/citologia , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos T/citologia
16.
Br J Haematol ; 180(6): 919-924, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29441563

RESUMO

Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.


Assuntos
Leucemia Mielomonocítica Aguda , Leucemia de Células T , Humanos , Leucemia Mielomonocítica Aguda/classificação , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/terapia , Leucemia de Células T/classificação , Leucemia de Células T/diagnóstico , Leucemia de Células T/genética , Leucemia de Células T/terapia , Células Mieloides , Proteínas de Neoplasias/genética , Células Precursoras de Linfócitos T
17.
J Immunol ; 200(6): 2046-2056, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29436414

RESUMO

The PU.1 transcription factor plays a critical role in the regulation of T cell development, so a report that it is dispensable for fetal thymopoiesis is puzzling. To understand this paradox, we examined the requirement for PU.1, encoded by Spi1, during fetal, neonatal, and adult thymopoiesis in a PU.1 hypomorphic mouse generated by deletion of the Spi1 14-kb upstream regulatory element and by analysis of patterns of gene expression in fetal and adult T cell progenitors. Our data demonstrate that the initiation of thymopoiesis during early gestation is less dependent on PU.1 compared with T cell differentiation in adults and that fetal T cell progenitors express lower levels of Spi1 compared with their adult counterparts. We also show that expression of the core network of T lineage transcription factors regulated by PU.1 differs in fetal and adult T cell progenitors. In particular, PU.1-regulated genes that promote T cell differentiation are differentially expressed in fetal versus adult early T lineage progenitors. These results indicate that the transcriptional differences between the fetal and adult T cell developmental programs are driven in part by differential levels of PU.1 expression and that this likely underlies the differences in the properties of fetal and adult T cell progenitors.


Assuntos
Linhagem da Célula/fisiologia , Feto/metabolismo , Feto/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T/fisiologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular/fisiologia , Expressão Gênica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Células Precursoras de Linfócitos T/fisiologia
18.
J Exp Med ; 215(2): 595-610, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29343500

RESUMO

Multipotent hematopoietic progenitors must acquire thymus-homing capacity to initiate T lymphocyte development. Despite its importance, the transcriptional program underlying this process remains elusive. Cbfß forms transcription factor complexes with Runx proteins, and here we show that Cbfß2, encoded by an RNA splice variant of the Cbfb gene, is essential for extrathymic differentiation of T cell progenitors. Furthermore, Cbfß2 endows extrathymic progenitors with thymus-homing capacity by inducing expression of the principal thymus-homing receptor, Ccr9. This occurs via direct binding of Cbfß2 to cell type-specific enhancers, as is observed in Rorγt induction during differentiation of lymphoid tissue inducer cells by activation of an intronic enhancer. As in mice, an alternative splicing event in zebrafish generates a Cbfß2-specific mRNA, important for ccr9 expression. Thus, despite phylogenetically and ontogenetically variable sites of origin of T cell progenitors, their robust thymus-homing capacity is ensured by an evolutionarily conserved mechanism emerging from functional diversification of Runx transcription factor complexes by acquisition of a novel splice variant.


Assuntos
Subunidade beta de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/imunologia , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/imunologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologia , Processamento Alternativo , Animais , Diferenciação Celular , Linhagem da Célula , Subunidades alfa de Fatores de Ligação ao Core/metabolismo , Subunidade beta de Fator de Ligação ao Core/deficiência , Elementos Facilitadores Genéticos , Evolução Molecular , Técnicas de Silenciamento de Genes , Camundongos , Camundongos Knockout , Camundongos Mutantes , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , RNA Mensageiro/genética , Receptores CCR/genética , Receptores CCR/imunologia , Especificidade da Espécie , Timo/citologia , Timo/embriologia , Timo/imunologia , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiência
19.
Zhonghua Xue Ye Xue Za Zhi ; 39(12): 977-982, 2018 Dec 14.
Artigo em Chinês | MEDLINE | ID: mdl-30612397

RESUMO

Objective: To analyze the clinical, laboratory characteristics and prognosis of adult early T-cell precursor acute lymphoblastic leukemia (ETP-ALL). Methods: The clinical data of 13 adult ETP-ALL patients from January 2009 to March 2017 were retrospectively analyzed and compared with non-ETP ALL patients. Results: 13 ETP-ALL patients (17.3%) were identified in 75 adult T-ALL patients, the median age of the patients was 35 years old (15 to 49 years) and 10 patients were male (76.9%). ETP-ALL patients had lower WBC count, LDH level, blasts in peripheral blood, lower incidence of thymic mass and higher PLT count compared to non-ETP ALL patients. The CR rate after one course induction chemotherapy for ETP-ALL and non-ETP ALL patients was 33.3% and 90.1%, respectively (χ(2)=26.521, P<0.001). The median overall survival(OS) was 11.33 (95%CI 0-28.46) and 25.69 (95%CI 11.98-39.41) months, respectively. The 3-year OS was 41.7% and 40.7%, respectively (P=0.699). The median event free survival (EFS) was 1.51 (95%CI 1.23-1.79) and 21.36 (95%CI 4.67-38.04) months, respectively. The 3-year EFS was 16.7% and 39.5%, respectively (P=0.002). The 3-year relapse free survival (RFS) was 53.0% and 52.0%, respectively (P=0.797). Multivariate analysis revealed that CNSL and allo-HSCT were independent risk factors affecting OS of T-ALL and ETP-ALL didn't affect the prognosis of T-ALL. Conclusion: To our knowledge, this study is the first report on characteristics and prognosis of adult ETP-ALL patients in China. At total of 13 T-ALL patients (17.3%) were classified as having ETP-ALL. These patients had a lower leukemia burden and lower CR rate after one course induction compared to non-ETP ALL patients. Allo-HSCT can improve the prognosis of ETP-ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adolescente , Adulto , China , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Precursoras de Linfócitos T , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Adulto Jovem
20.
J Pediatr Hematol Oncol ; 40(1): e34-e37, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28538509

RESUMO

We reviewed the immunophenotypic subtypes of pediatric T-cell lymphoblastic lymphoma in the Japanese Pediatric Leukemia/Lymphoma Study Group ALB-NHL03 study. Of the 104 patients, 40 patients each had sufficient data to evaluate the immunophenotypes and early T-cell precursor (ETP) subtype. Pro-T, pre-T, intermediate T, and mature T cells were observed in 1, 9, 21, and 9 cases, respectively. The 3-year event-free survival (EFS) rates of those with pro-T/pre-T, intermediate T, and mature T cells were 80.0±12.6%, 71.4±9.9%, and 88.9±10.5%, respectively (P=0.546). There were 8 and 32 cases of ETP and non-ETP subtypes, with 3-year EFS rates of 75.0±15.3% and 71.9±8.0%, respectively (P=0.828), indicating that the immunophenotypic subtype was not predictive of EFS in this study.


Assuntos
Células Precursoras de Linfócitos T/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Prognóstico , Criança , Feminino , Humanos , Imunofenotipagem , Japão , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Estudos Retrospectivos , Análise de Sobrevida , Subpopulações de Linfócitos T/patologia
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