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Nat Immunol ; 21(6): 660-670, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32341509


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.

Nat Immunol ; 20(10): 1393-1403, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31477919


In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet how the pre-BCR mediates these functions remains unclear. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 ligation by C-X-C motif chemokine ligand 12 activates the mitogen-activated protein kinase extracellular-signal-regulated kinase, which then directs the development of small pre- and immature B cells, including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, pre-BCR expression and escape from interleukin-7 have only modest effects on B cell developmental transcriptional and epigenetic programs. These data show a direct and central role for CXCR4 in orchestrating late B cell lymphopoiesis. Furthermore, in the context of previous findings, our data provide a three-receptor system sufficient to recapitulate the essential features of B lymphopoiesis in vitro.

Linfócitos B/imunologia , Cadeias kappa de Imunoglobulina/genética , Células Precursoras de Linfócitos B/fisiologia , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores CXCR4/metabolismo , Animais , Pontos de Checagem do Ciclo Celular , Células Cultivadas , Quimiocina CXCL12/metabolismo , Feminino , Fatores Reguladores de Interferon/genética , Linfopoese , Masculino , Camundongos , Receptores de Antígenos de Linfócitos B/genética , Receptores CXCR4/genética , Recombinação Genética
J Immunol ; 202(10): 2837-2842, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30962294


Lymphoid specification is the process by which hematopoietic stem cells (HSCs) and their progeny become restricted to differentiation through the lymphoid lineages. The basic helix-loop-helix transcription factors E2A and Lyl1 form a complex that promotes lymphoid specification. In this study, we demonstrate that Tal1, a Lyl1-related basic helix-loop-helix transcription factor that promotes T acute lymphoblastic leukemia and is required for HSC specification, erythropoiesis, and megakaryopoiesis, is a negative regulator of murine lymphoid specification. We demonstrate that Tal1 limits the expression of multiple E2A target genes in HSCs and controls the balance of myeloid versus T lymphocyte differentiation potential in lymphomyeloid-primed progenitors. Our data provide insight into the mechanisms controlling lymphocyte specification and may reveal a basis for the unique functions of Tal1 and Lyl1 in T acute lymphoblastic leukemia.

Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Diferenciação Celular/imunologia , Células Progenitoras Linfoides/imunologia , Células Progenitoras Mieloides/imunologia , Proteínas de Neoplasias/imunologia , Proteína 1 de Leucemia Linfocítica Aguda de Células T/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/genética , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T/genética
Nat Immunol ; 19(12): 1366-1378, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420627


Thymocyte development requires a complex orchestration of multiple transcription factors. Ablating either TCF-1 or HEB in CD4+CD8+ thymocytes elicits similar developmental outcomes including increased proliferation, decreased survival, and fewer late Tcra rearrangements. Here, we provide a mechanistic explanation for these similarities by showing that TCF-1 and HEB share ~7,000 DNA-binding sites genome wide and promote chromatin accessibility. The binding of both TCF-1 and HEB was required at these shared sites for epigenetic and transcriptional gene regulation. Binding of TCF-1 and HEB to their conserved motifs in the enhancer regions of genes associated with T cell differentiation promoted their expression. Binding to sites lacking conserved motifs in the promoter regions of cell-cycle-associated genes limited proliferation. TCF-1 displaced nucleosomes, allowing for chromatin accessibility. Importantly, TCF-1 inhibited Notch signaling and consequently protected HEB from Notch-mediated proteasomal degradation. Thus, TCF-1 shifts nucleosomes and safeguards HEB, thereby enabling their cooperation in establishing the epigenetic and transcription profiles of CD4+CD8+ thymocytes.

Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Regulação da Expressão Gênica/imunologia , Fator 1-alfa Nuclear de Hepatócito/imunologia , Linfopoese/imunologia , Timócitos/imunologia , Animais , Antígenos CD4/imunologia , Antígenos CD8/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
Nat Commun ; 9(1): 3888, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250168


Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development.

Agamaglobulinemia/genética , Proteínas de Transporte/metabolismo , Epigênese Genética/fisiologia , Linfopoese/genética , Proteínas Nucleares/metabolismo , Adolescente , Adulto , Agamaglobulinemia/sangue , Animais , Proteínas de Transporte/genética , Diferenciação Celular/genética , Criança , Elementos Facilitadores Genéticos/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/fisiologia , Humanos , Leucócitos Mononucleares , Masculino , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Células Precursoras de Linfócitos B , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Interferente Pequeno/metabolismo , Análise de Sequência de RNA , Sequenciamento Completo do Exoma