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1.
Commun Biol ; 4(1): 563, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980982

RESUMO

Innate Lymphoid Cells (ILCs) are immune cells typically found on mucosal surfaces and in secondary lymphoid organs where they regulate the immune response to pathogens. Despite their key role in the immune response, there are still fundamental gaps in our understanding of ILCs. Here we report a human ILC population present in the follicles of tonsils and lymph nodes termed follicular regulatory ILCs (ILCFR) that to our knowledge has not been previously identified. ILCFR have a distinct phenotype and transcriptional program when compared to other defined ILCs. Surprisingly, ILCFR inhibit the ability of follicular helper T (Tfh) cells to provide B cell help. The localization of ILCFR to the germinal centers suggests these cells may interfere with germinal center B cell (GC-B) and germinal center Tfh cell (GC-Tfh) interactions through the production of transforming growth factor beta (TGF-ß. Intriguingly, under conditions of impaired GC-Tfh-GC-B cell interactions, such as human immunodeficiency virus (HIV) infection, the frequency of these cells is increased. Overall, we predict a role for ILCFR in regulating GC-Tfh-GC-B cell interactions and propose they expand in chronic inflammatory conditions.


Assuntos
Centro Germinativo/imunologia , Centro Germinativo/fisiologia , Linfócitos/imunologia , Adolescente , Adulto , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Imunidade Inata/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Ativação Linfocitária/imunologia , Linfócitos/metabolismo , Masculino , Tonsila Palatina/imunologia , Tonsila Palatina/metabolismo , Células T Auxiliares Foliculares/imunologia
2.
Front Immunol ; 12: 659151, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868306

RESUMO

Protective high affinity antibody responses emerge through an orchestrated developmental process that occurs in germinal centers (GCs). While GCs have been appreciated since 1930, a wealth of recent progress provides new insights into the molecular and cellular dynamics governing humoral immunity. In this review, we highlight advances that demonstrate that fundamental GC B cell function, selection, proliferation and SHM occur within distinct cell states. The resulting new model provides new opportunities to understand the evolution of immunity in infectious, autoimmune and neoplastic diseases.


Assuntos
Centro Germinativo/citologia , Centro Germinativo/fisiologia , Animais , Formação de Anticorpos , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Humanos , Imunidade Humoral , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia
3.
Nat Immunol ; 21(6): 660-670, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341509

RESUMO

Within germinal centers (GCs), complex and highly orchestrated molecular programs must balance proliferation, somatic hypermutation and selection to both provide effective humoral immunity and to protect against genomic instability and neoplastic transformation. In contrast to this complexity, GC B cells are canonically divided into two principal populations, dark zone (DZ) and light zone (LZ) cells. We now demonstrate that, following selection in the LZ, B cells migrated to specialized sites within the canonical DZ that contained tingible body macrophages and were sites of ongoing cell division. Proliferating DZ (DZp) cells then transited into the larger DZ to become differentiating DZ (DZd) cells before re-entering the LZ. Multidimensional analysis revealed distinct molecular programs in each population commensurate with observed compartmentalization of noncompatible functions. These data provide a new three-cell population model that both orders critical GC functions and reveals essential molecular programs of humoral adaptive immunity.


Assuntos
Microambiente Celular/genética , Microambiente Celular/imunologia , Centro Germinativo/citologia , Centro Germinativo/fisiologia , Animais , Biomarcadores , Biologia Computacional/métodos , Imunofluorescência , Perfilação da Expressão Gênica , Genômica/métodos , Camundongos , Fosforilação , Proteoma , Proteômica/métodos , Transcriptoma
4.
Elife ; 92020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32204792

RESUMO

Germinal centres (GCs) are T follicular helper cell (Tfh)-dependent structures that form in response to vaccination, producing long-lived antibody secreting plasma cells and memory B cells that protect against subsequent infection. With advancing age the GC and Tfh cell response declines, resulting in impaired humoral immunity. We sought to discover what underpins the poor Tfh cell response in ageing and whether it is possible to correct it. Here, we demonstrate that older people and aged mice have impaired Tfh cell differentiation upon vaccination. This deficit is preceded by poor activation of conventional dendritic cells type 2 (cDC2) due to reduced type 1 interferon signalling. Importantly, the Tfh and cDC2 cell response can be boosted in aged mice by treatment with a TLR7 agonist. This demonstrates that age-associated defects in the cDC2 and Tfh cell response are not irreversible and can be enhanced to improve vaccine responses in older individuals.


Assuntos
Centro Germinativo/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Células T Auxiliares Foliculares/fisiologia , Linfócitos T Auxiliares-Indutores/fisiologia , Adolescente , Transferência Adotiva , Adulto , Idoso , Envelhecimento , Animais , Linfócitos B , Células da Medula Óssea , Antígenos CD11/genética , Antígenos CD11/metabolismo , Quimera , Feminino , Humanos , Imunidade Humoral , Memória Imunológica , Vacinas contra Influenza/administração & dosagem , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/veterinária , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Vacinação , Adulto Jovem
5.
APMIS ; 128(4): 308-315, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31991488

RESUMO

EZH2 is an important epigenetic regulator, but its role in diffuse large B-cell lymphoma (DLBCL) pathogenesis and its relationship with MYC, BCL2, and TP53 expression, chromosomal rearrangements, and clinical features are still poorly understood. So, we investigated EZH2 expression and its associations with the immunophenotypic presentations, including MYC, BCL2, and TP53 expression, MYC, BCL2, and BCL6 translocation status, clinicopathological features, and therapeutic response to R-CHOP in a series of 139 DLBCL cases. EZH2 positivity was associated with MYC and TP53 expression (p = 0.0002 and p = 0.0000, respectively) and to high proliferative index (Ki67>70%, p = 0.0082). No associations were found among EZH2 expression and chromosomal translocation status. The non-germinal center (nGC) DLBCL presented most of associations observed in the general sample; however, only TP53 immunodetection showed associations with EZH2 expression in the germinal center (GC) DLBCL. EZH2 expression had no impact on therapeutic efficacy in R-CHOP-treated patients. In conclusion, EZH2 seems to be upregulated by MYC, to rely on TP53 alterations, and is associated with high proliferative tumors in DLBCL, which might be dependent on GC or nGC subclassifications. Furthermore, it is not a therapeutic efficacy marker to R-CHOP in our series.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Centro Germinativo/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Translocação Genética/genética , Regulação para Cima/genética , Adulto Jovem
6.
J Exp Med ; 217(3)2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-31873727

RESUMO

Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate BCR functions in GCs is unclear. Here, we found that Syk degradation restrains plasma cell (PC) formation in GCs and promotes B cell LZ to DZ transition. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates BCR signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting the expression of PC transcription factors in GC B cells. Inhibition of Syk degradation perturbed gene expression, specifically in the LZ, and enhanced the generation of PCs without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulates cell fate within specialized microanatomical sites.


Assuntos
Centro Germinativo/metabolismo , Plasmócitos/metabolismo , Quinase Syk/metabolismo , Animais , Linfócitos B/metabolismo , Linfócitos B/fisiologia , Proliferação de Células/fisiologia , Expressão Gênica/fisiologia , Centro Germinativo/fisiologia , Ativação Linfocitária/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmócitos/fisiologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/fisiologia
7.
Immunity ; 51(3): 535-547.e9, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31519498

RESUMO

Inactivating mutations of the CREBBP and EP300 acetyltransferases are among the most common genetic alterations in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). Here, we examined the relationship between these two enzymes in germinal center (GC) B cells, the normal counterpart of FL and DLBCL, and in lymphomagenesis by using conditional GC-directed deletion mouse models targeting Crebbp or Ep300. We found that CREBBP and EP300 modulate common as well as distinct transcriptional programs implicated in separate anatomic and functional GC compartments. Consistently, deletion of Ep300 but not Crebbp impaired the fitness of GC B cells in vivo. Combined loss of Crebbp and Ep300 completely abrogated GC formation, suggesting that these proteins partially compensate for each other through common transcriptional targets. This synthetic lethal interaction was retained in CREBBP-mutant DLBCL cells and could be pharmacologically targeted with selective small molecule inhibitors of CREBBP and EP300 function. These data provide proof-of-principle for the clinical development of EP300-specific inhibitors in FL and DLBCL.


Assuntos
Linfócitos B/fisiologia , Proteína de Ligação a CREB/genética , Proteína p300 Associada a E1A/genética , Epigênese Genética/genética , Centro Germinativo/fisiologia , Linfoma Folicular/etiologia , Linfoma Difuso de Grandes Células B/genética , Acetiltransferases/genética , Animais , Linhagem Celular , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Deleção de Sequência/genética , Transcrição Genética/genética
8.
J Immunol ; 203(6): 1493-1501, 2019 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-31399517

RESUMO

During somatic hypermutation (SHM) of Ig genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase are processed by multiple error-prone repair pathways. Although error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at activation-induced cytidine deaminase off-target genes, its role at the hypermutating Ig locus in the germinal center is unexplored. Using B cell-specific inactivation of the critical HR factor Brca2, we detected decreased proliferation, survival, and thereby class switching of ex vivo-activated B cells. Intriguingly, an HR defect allowed for a germinal center reaction and affinity maturation in vivo, albeit at reduced amounts. Analysis of SHM revealed that a certain fraction of DNA lesions at C:G bp was indeed repaired in an error-free manner via Brca2 instead of being processed by error-prone translesion polymerases. By applying a novel pseudo-time in silico analysis of mutational processes, we found that the activity of A:T mutagenesis during SHM increased during a germinal center reaction, but this was in part defective in Brca2-deficient mice. These mutation pattern changes in Brca2-deficient B cells were mostly specific for the Ig V region, suggesting a local or time-dependent need for recombination repair to survive high rates of SHM and especially A:T mutagenesis.


Assuntos
Centro Germinativo/fisiologia , Recombinação Homóloga/genética , Mutação/genética , Animais , Linfócitos B/fisiologia , Proteína BRCA2/genética , Citidina Desaminase/genética , DNA/genética , Dano ao DNA/genética , Feminino , Genes de Imunoglobulinas/genética , Ativação Linfocitária/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hipermutação Somática de Imunoglobulina/genética
9.
J Immunol ; 202(11): 3137-3142, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31028119

RESUMO

The DNA damage response protein ATM has long been known to influence class switch recombination in ex vivo-cultured B cells. However, an assessment of B cell-intrinsic requirement of ATM in humoral responses in vivo was confounded by the fact that its germline deletion affects T cell function, and B:T cell interactions are critical for in vivo immune responses. In this study, we demonstrate that B cell-specific deletion of ATM in mice leads to reduction in germinal center (GC) frequency and size in response to immunization. We find that loss of ATM induces apoptosis of GC B cells, likely due to unresolved DNA lesions in cells attempting to undergo class-switch recombination. Accordingly, suboptimal GC responses in ATM-deficient animals are characterized by decreased titers of class-switched Abs and decreased rates of somatic hypermutation. These results unmask the critical B cell-intrinsic role of ATM in maintaining an optimal GC response following immunization.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linfócitos B/fisiologia , Centro Germinativo/fisiologia , Linfócitos T/fisiologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Células Cultivadas , Reparo do DNA/genética , Switching de Imunoglobulina , Camundongos , Camundongos Knockout , Receptores de Complemento 3d/genética , Hipermutação Somática de Imunoglobulina
10.
EMBO J ; 38(11)2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31015337

RESUMO

In contrast to other B-cell antigen receptor (BCR) classes, the function of IgD BCR on mature B cells remains largely elusive as mature B cells co-express IgM, which is sufficient for development, survival, and activation of B cells. Here, we show that IgD expression is regulated by the forkhead box transcription factor FoxO1, thereby shifting the responsiveness of mature B cells towards recognition of multivalent antigen. FoxO1 is repressed by phosphoinositide 3-kinase (PI3K) signaling and requires the lipid phosphatase Pten for its activation. Consequently, Pten-deficient B cells expressing knock-ins for BCR heavy and light chain genes are unable to upregulate IgD. Furthermore, in the presence of autoantigen, Pten-deficient B cells cannot eliminate the autoreactive BCR specificity by secondary light chain gene recombination. Instead, Pten-deficient B cells downregulate BCR expression and become unresponsive to further BCR-mediated stimulation. Notably, we observed a delayed germinal center (GC) reaction by IgD-deficient B cells after immunization with trinitrophenyl-ovalbumin (TNP-Ova), a commonly used antigen for T-cell-dependent antibody responses. Together, our data suggest that the activation of IgD expression by Pten/FoxO1 results in mature B cells that are selectively responsive to multivalent antigen and are capable of initiating rapid GC reactions and T-cell-dependent antibody responses.


Assuntos
Linfócitos B/fisiologia , Centro Germinativo/fisiologia , Imunoglobulina D/genética , PTEN Fosfo-Hidrolase/fisiologia , Receptores de Antígenos de Linfócitos B/genética , Animais , Células Cultivadas , Proteína Forkhead Box O1/fisiologia , Regulação da Expressão Gênica/imunologia , Centro Germinativo/metabolismo , Imunoglobulina D/imunologia , Imunoglobulina D/metabolismo , Camundongos , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia
11.
Immunol Rev ; 288(1): 240-261, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30874347

RESUMO

B cell lymphomas comprise a heterogeneous group of genetically, biologically, and clinically distinct neoplasms that, in most cases, originate from the clonal expansion of B cells in the germinal center (GC). In recent years, the advent of novel genomics technologies has revolutionized our understanding of the molecular pathogenesis of lymphoid malignancies as a multistep process that requires the progressive accumulation of multiple genetic and epigenetic alterations. A common theme that emerged from these studies is the ability of lymphoma cells to co-opt the same biological programs and signal transduction networks that operate during the normal GC reaction, and misuse them for their own survival advantage. This review summarizes recent progress in the understanding of the genetic and epigenetic mechanisms that drive the malignant transformation of GC B cells. These insights provide a conceptual framework for the identification of cellular pathways that may be explored for precision medicine approaches.


Assuntos
Linfócitos B/fisiologia , Centro Germinativo/fisiologia , Linfoma de Células B/genética , Animais , Transformação Celular Neoplásica , Reprogramação Celular , Epigênese Genética , Regulação Leucêmica da Expressão Gênica , Humanos , Linfoma de Células B/metabolismo , Transdução de Sinais
12.
PLoS Pathog ; 15(3): e1007311, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30897187

RESUMO

CD8+ T cells play an important role in controlling of HIV and SIV infections. However, these cells are largely excluded from B cell follicles where HIV and SIV producing cells concentrate during chronic infection. It is not known, however, if antigen-specific CD8+ T cells are excluded gradually as pathogenesis progresses from early to chronic phase, or this phenomenon occurs from the beginning infection. In this study we determined that SIV-specific CD8+ T cells were largely excluded from follicles during early infection, we also found that within follicles, they were entirely absent in 60% of the germinal centers (GCs) examined. Furthermore, levels of SIV-specific CD8+ T cells in follicular but not extrafollicular areas significantly correlated inversely with levels of viral RNA+ cells. In addition, subsets of follicular SIV-specific CD8+ T cells were activated and proliferating and expressed the cytolytic protein perforin. These studies suggest that a paucity of SIV-specific CD8+ T cells in follicles and complete absence within GCs during early infection may set the stage for the establishment of persistent chronic infection.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Centro Germinativo/fisiologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Doença Aguda , Animais , Linfócitos B/fisiologia , Linfócitos T CD8-Positivos/metabolismo , Centro Germinativo/imunologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/fisiopatologia , Vírus da Imunodeficiência Símia/imunologia , Carga Viral/imunologia , Replicação Viral
13.
Cancer Discov ; 9(5): 662-679, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30777872

RESUMO

Several lines of evidence link the canonical oncogene BCL6 to stress response. Here we demonstrate that BCL6 evolved in vertebrates as a component of the HSF1-driven stress response, which has been co-opted by the immune system to support germinal center formation and may have been decisive in the convergent evolution of humoral immunity in jawless and jawed vertebrates. We find that the highly conserved BTB corepressor binding site of BCL6 mediates stress adaptation across vertebrates. We demonstrate that pan-cancer cells hijack this stress tolerance mechanism to aberrantly express BCL6. Targeting the BCL6 BTB domain in cancer cells induces apoptosis and increases susceptibility to repeated doses of cytotoxic therapy. The chemosensitization effect upon BCL6 BTB inhibition is dependent on the derepression of TOX, implicating modulation of DNA repair as a downstream mechanism. Collectively, these data suggest a form of adaptive nononcogene addiction rooted in the natural selection of BCL6 during vertebrate evolution. SIGNIFICANCE: We demonstrate that HSF1 drives BCL6 expression to enable stress tolerance in vertebrates. We identify an HSF1-BCL6-TOX stress axis that is required by cancer cells to tolerate exposure to cytotoxic agents and points toward BCL6-targeted therapy as a way to more effectively kill a wide variety of solid tumors.This article is highlighted in the In This Issue feature, p. 565.


Assuntos
Adaptação Fisiológica/fisiologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Estresse Fisiológico/fisiologia , Animais , Apoptose/fisiologia , Linfócitos B/citologia , Linfócitos B/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Feminino , Centro Germinativo/citologia , Centro Germinativo/fisiologia , Fatores de Transcrição de Choque Térmico/biossíntese , Fatores de Transcrição de Choque Térmico/genética , Fatores de Transcrição de Choque Térmico/metabolismo , Resposta ao Choque Térmico , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Neoplasias/enzimologia , Neoplasias/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genética
14.
Nat Commun ; 10(1): 22, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604754

RESUMO

Mechanisms regulating B cell development, activation, education in the germinal center (GC) and differentiation, underpin the humoral immune response. Protein arginine methyltransferase 5 (Prmt5), which catalyzes most symmetric dimethyl arginine protein modifications, is overexpressed in B cell lymphomas but its function in normal B cells is poorly defined. Here we show that Prmt5 is necessary for antibody responses and has essential but distinct functions in all proliferative B cell stages in mice. Prmt5 is necessary for B cell development by preventing p53-dependent and p53-independent blocks in Pro-B and Pre-B cells, respectively. By contrast, Prmt5 protects, via p53-independent pathways, mature B cells from apoptosis during activation, promotes GC expansion, and counters plasma cell differentiation. Phenotypic and RNA-seq data indicate that Prmt5 regulates GC light zone B cell fate by regulating transcriptional programs, achieved in part by ensuring RNA splicing fidelity. Our results establish Prmt5 as an essential regulator of B cell biology.


Assuntos
Linfócitos B/fisiologia , Proliferação de Células/fisiologia , Centro Germinativo/fisiologia , Imunidade Humoral/fisiologia , Proteína-Arginina N-Metiltransferases/fisiologia , Animais , Apoptose/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Centro Germinativo/citologia , Humanos , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Cultura Primária de Células , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais/fisiologia , Trichostrongyloidea/imunologia , Tricostrongiloidíase/imunologia , Tricostrongiloidíase/parasitologia , Proteína Supressora de Tumor p53/metabolismo
15.
Brain Behav Immun ; 76: 48-60, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30414952

RESUMO

Germinal centers (GC) are vital to adaptive immunity. BCL6 and miR-155 are implicated in control of GC reaction and lymphomagenesis. FBXO11 causes BCL6 degradation through ubiquitination in B-cell lymphomas. Chronic psychological stress is known to drive immunosuppression. Corticosterone (CORT) is an adrenal hormone expressed in response to stress and can similarly impair immune functions. However, whether GC formation is disrupted by chronic psychological stress and its molecular mechanism remain to be elucidated. To address this issue, we established a GC formation model in vivo, and a GC B cell differentiation model in vitro. Comparing Naive B cells to GC B cells in vivo and in vitro, the differences of BCL6 and FBXO11 mRNA do not match the changes at the protein level and miR-155 levels that were observed. Next we demonstrated that CORT increase, induced by chronic psychological stress, reduced GC response, IgG1 antibody production and miR-155 level in vivo. The effect of chronic psychological stress can be blocked by a glucocorticoid receptor (GR) antagonist. Similarly, impaired GC B cell generation and isotope class switching were observed. Furthermore, we found that miR-155 and BCL6 expression were downregulated, but FBXO11 expression was upregulated in GC B cells treated with CORT in vitro. In addition, we demonstrated that miR-155 directly down-regulated FBXO11 expression by binding to its 3́-untranslated region. The subsequent overexpression of miR-155 significantly blocked the stress-induced impairment of GC response, due to changes in FBXO11 and BCL6 expression, as well as increased apoptosis in B cells both in vivo and in vitro. Our findings suggest perturbation of GC reaction may play a role in chronic psychological stress-induced immunosuppression through a glucocorticoid pathway, and miR-155-mediated post-transcriptional regulation of FBXO11 and BCL6 expression may contribute to the impaired GC response.


Assuntos
Centro Germinativo/metabolismo , MicroRNAs/metabolismo , Estresse Psicológico/metabolismo , Animais , Apoptose/fisiologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/genética , Proteínas F-Box/metabolismo , Feminino , Centro Germinativo/fisiologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Estresse Psicológico/fisiopatologia
16.
Front Immunol ; 9: 2026, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30233601

RESUMO

Germinal centers (GCs) are essential structures of the humoral immune response, which form in the periphery in response to T cell dependent antigens. During the GC reaction, B cells undergo critical differentiation steps, which ultimately lead to the generation of antibodies with altered effector function and higher affinity for the selected antigen. Remarkably, many of the B cell tumors have their origin in the GCs; thus, understanding how the formation of these structures is regulated or deregulated is of high medical importance. This review gives an overview of the transcription factors that have been linked to the generation of GCs, and of their roles in the process.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/fisiologia , Imunidade Humoral , Linfoma de Células B/imunologia , Plasmócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/metabolismo , Animais , Carcinogênese , Diferenciação Celular , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição/genética
17.
Elife ; 72018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30066671

RESUMO

Understanding cellular processes occurring in vivo on time scales of days to weeks requires repeatedly interrogating the same tissue without perturbing homeostasis. We describe a novel setup for longitudinal intravital imaging of murine peripheral lymph nodes (LNs). The formation and evolution of single germinal centers (GCs) was visualized over days to weeks. Naïve B cells encounter antigen and form primary foci, which subsequently seed GCs. These experience widely varying rates of homogenizing selection, even within closely confined spatial proximity. The fluidity of GCs is greater than previously observed with large shifts in clonality over short time scales; and loss of GCs is a rare, observable event. The observation of contemporaneous, congruent shifts in clonal composition between GCs within the same animal suggests inter-GC trafficking of memory B cells. This tool refines approaches to resolving immune dynamics in peripheral LNs with high temporospatial resolution and minimal perturbation of homeostasis.


Assuntos
Linfócitos B/imunologia , Evolução Clonal , Seleção Clonal Mediada por Antígeno/imunologia , Centro Germinativo/citologia , Linfonodos/citologia , Animais , Linfócitos B/citologia , Linfócitos B/fisiologia , Movimento Celular , Células Cultivadas , Centro Germinativo/imunologia , Centro Germinativo/fisiologia , Linfonodos/imunologia , Linfonodos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Imagem com Lapso de Tempo
18.
Nat Immunol ; 19(9): 1013-1024, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30104629

RESUMO

Most adult B cell lymphomas originate from germinal center (GC) B cells, but it is unclear to what extent B cells in overt lymphoma retain the functional dynamics of GC B cells or are blocked at a particular stage of the GC reaction. Here we used integrative single-cell analysis of phenotype, gene expression and variable-region sequence of the immunoglobulin heavy-chain locus to track the characteristic human GC B cell program in follicular lymphoma B cells. By modeling the cyclic continuum of GC B cell transitional states, we identified characteristic patterns of synchronously expressed gene clusters. GC-specific gene-expression synchrony was lost in single lymphoma B cells. However, distinct follicular lymphoma-specific cell states co-existed within single patient biopsies. Our data show that lymphoma B cells are not blocked in a GC B cell state but might adopt new dynamic modes of functional diversity, which opens the possibility of novel definitions of lymphoma identity.


Assuntos
Subpopulações de Linfócitos B/fisiologia , Linfócitos B/fisiologia , Centro Germinativo/fisiologia , Região Variável de Imunoglobulina/genética , Linfoma de Células B/genética , Adulto , Diferenciação Celular , Células Cultivadas , Feminino , Regulação Neoplásica da Expressão Gênica , Centro Germinativo/patologia , Humanos , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise de Célula Única , Transcriptoma/genética
19.
Nat Immunol ; 19(9): 1025-1034, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30082831

RESUMO

Memory B cells (Bmem cells) are the basis of long-lasting humoral immunity. They respond to re-encountered antigens by rapidly producing specific antibodies and forming germinal centers (GCs), a recall response that has been known for decades but remains poorly understood. We found that the receptor for the cytokine IL-9 (IL-9R) was induced selectively on Bmem cells after primary immunization and that IL-9R-deficient mice exhibited a normal primary antibody response but impaired recall antibody responses, with attenuated population expansion and plasma-cell differentiation of Bmem cells. In contrast, there was augmented GC formation, possibly due to defective downregulation of the ligand for the co-stimulatory receptor ICOS on Bmem cells. A fraction of Bmem cells produced IL-9. These findings indicate that IL-9R signaling in Bmem cells regulates humoral recall responses.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/fisiologia , Interleucina-9/metabolismo , Plasmócitos/imunologia , Receptores de Interleucina-9/genética , Animais , Diferenciação Celular , Células Cultivadas , Imunidade Humoral , Imunização Secundária , Região Variável de Imunoglobulina/genética , Memória Imunológica , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-9/metabolismo , Transdução de Sinais
20.
Nat Immunol ; 19(9): 986-1000, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30127432

RESUMO

Gain-of-function mutations in the gene encoding the phosphatidylinositol-3-OH kinase catalytic subunit p110δ (PI3Kδ) result in a human primary immunodeficiency characterized by lymphoproliferation, respiratory infections and inefficient responses to vaccines. However, what promotes these immunological disturbances at the cellular and molecular level remains unknown. We generated a mouse model that recapitulated major features of this disease and used this model and patient samples to probe how hyperactive PI3Kδ fosters aberrant humoral immunity. We found that mutant PI3Kδ led to co-stimulatory receptor ICOS-independent increases in the abundance of follicular helper T cells (TFH cells) and germinal-center (GC) B cells, disorganized GCs and poor class-switched antigen-specific responses to immunization, associated with altered regulation of the transcription factor FOXO1 and pro-apoptotic and anti-apoptotic members of the BCL-2 family. Notably, aberrant responses were accompanied by increased reactivity to gut bacteria and a broad increase in autoantibodies that were dependent on stimulation by commensal microbes. Our findings suggest that proper regulation of PI3Kδ is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome.


Assuntos
Linfócitos B/fisiologia , Microbioma Gastrointestinal/imunologia , Centro Germinativo/fisiologia , Mutação/genética , Fosfatidilinositol 3-Quinases/genética , Linfócitos T Auxiliares-Indutores/fisiologia , Animais , Autoanticorpos/sangue , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/genética , Modelos Animais de Doenças , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Imunidade Humoral/genética , Switching de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
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