RESUMO
Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with longevity influenced by intrinsic factors like the immunoglobulin isotype. Analysis at single-cell resolution revealed that the bone marrow is unique in housing a compendium of PCs generated all over the body that retain aspects of the transcriptional program indicative of their tissue of origin. This study reveals that extreme longevity is an intrinsic property of TrPCs whose transcriptome is imprinted by signals received both at the site of induction and within the tissue of residence.
Assuntos
Medula Óssea , Plasmócitos , Células da Medula ÓsseaRESUMO
A complete chart of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of differentiation and function of an organ system. We generated matched epigenome and transcriptome measurements in 86 primary cell types that span the mouse immune system and its differentiation cascades. This breadth of data enable variance components analysis that suggests that genes fall into two distinct classes, controlled by either enhancer- or promoter-driven logic, and multiple regression that connects genes to the enhancers that regulate them. Relating transcription factor (TF) expression to the genome-wide accessibility of their binding motifs classifies them as predominantly openers or closers of local chromatin accessibility, pinpointing specific cis-regulatory elements where binding of given TFs is likely functionally relevant, validated by chromatin immunoprecipitation sequencing (ChIP-seq). Overall, this cis-regulatory atlas provides a trove of information on transcriptional regulation through immune differentiation and a foundational scaffold to define key regulatory events throughout the immunological genome.
Assuntos
Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Elementos Reguladores de Transcrição/genética , Animais , Sítios de Ligação/genética , Cromatina , Imunoprecipitação da Cromatina/métodos , Elementos Facilitadores Genéticos/genética , Epigenômica/métodos , Regulação da Expressão Gênica/genética , Camundongos , Camundongos Endogâmicos C57BL , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genéticaRESUMO
Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP-VIPR2 pathway in ILC3s.
Assuntos
Imunidade nas Mucosas/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Periodicidade , Peptídeo Intestinal Vasoativo/imunologia , Animais , Ingestão de Alimentos/imunologia , Imunidade Inata/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo Intestinal Vasoativo/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Plasma cell differentiation requires silencing of B cell transcription, while it establishes antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for the generation of plasma cells; however, their function in mature plasma cells has remained elusive. We found that while IRF4 was essential for the survival of plasma cells, Blimp-1 was dispensable for this. Blimp-1-deficient plasma cells retained their transcriptional identity but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap in the functions of Blimp-1 and XBP-1 was restricted to that response, with Blimp-1 uniquely regulating activity of the kinase mTOR and the size of plasma cells. Thus, Blimp-1 was required for the unique physiological ability of plasma cells that enables the secretion of protective antibody.
Assuntos
Diferenciação Celular/imunologia , Imunoglobulinas/imunologia , Fatores Reguladores de Interferon/imunologia , Plasmócitos/imunologia , Fatores de Transcrição/imunologia , Resposta a Proteínas não Dobradas/imunologia , Fator 6 Ativador da Transcrição/genética , Fator 6 Ativador da Transcrição/imunologia , Animais , Tamanho Celular , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Imunoglobulinas/metabolismo , Fatores Reguladores de Interferon/genética , Camundongos , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Fatores de Transcrição de Fator Regulador X , Análise de Sequência de DNA , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-BoxRESUMO
FoxP3-expressing regulatory T (Treg) cells are essential for maintaining immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly expresses genes critical for Treg cell function, although how this process is coordinated on a transcriptional level is poorly understood. Here, we demonstrate that mice lacking the transcription factor Myb in Treg cells succumbed to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and genomic footprint analyses revealed that Myb directly regulated a large proportion of the gene expression specific to effector Treg cells, identifying Myb as a critical component of the gene regulatory network controlling effector Treg cell differentiation and function.
Assuntos
Redes Reguladoras de Genes/imunologia , Homeostase/imunologia , Ativação Linfocitária/imunologia , Proteínas Proto-Oncogênicas c-myb/imunologia , Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , TranscriptomaRESUMO
The plasma cells (PC) are characterized by their rarity, their formidable capacity to continuously secrete massive amounts of antibodies and the potential to live through the whole life span of the organism that houses them. Because of the potency of their effector function, their differentiation and survival are tightly regulated. The PC identity is implemented and maintained by a transcriptional program that allow them to face the challenges entailed by their longevity and high metabolic activity. The main transcription factors overseeing this transcriptional network have been identified (BLIMP1, IRF4, XBP1), but new players, like miRNA, continue to emerge and bring new layers of complexity to the regulatory loops. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2021. 51: 1089-1109], Pracht et al. identify miR-148a as a significant actor of the PC program that favors the differentiation through the inhibition of competitor fates, and supports the survival and fitness of the long-lived PC. In this commentary, we will discuss the place of miR-148a in the PC transcriptional network and its potential as a therapeutic target in PC-driven diseases.
Assuntos
MicroRNAs , Plasmócitos , Diferenciação Celular , Redes Reguladoras de Genes , MicroRNAs/genéticaRESUMO
Antibodies are an essential component of our immune system, underpinning the effectiveness of both the primary immune response to microbial pathogens and the protective and long-lived immunity against re-challenge. All antibodies are produced by relatively rare populations of plasmablasts and plasma cells, collectively termed antibody-secreting cells (ASCs). It is now apparent that ASCs are unique in the body in terms of their gene expression program and metabolic pathways that enable these cells to have an extraordinary rate of immunoglobulin gene transcription, translation, assembly and secretion. In this review we will discuss the cellular, metabolic and molecular specialization that allows ASCs to maintain such high rates of antibody production, in some cases for the life of the individual. Throughout the review we will link these exquisite cellular and molecular adaptations to the major regulators of ASC gene expression, in an attempt to define how the ASC phenotype and function is genetically programmed.
Assuntos
Células Produtoras de Anticorpos/imunologia , Linfócitos B/imunologia , Plasmócitos/imunologia , Animais , Formação de Anticorpos , Diferenciação Celular , Regulação da Expressão Gênica , Humanos , Imunoglobulinas/metabolismoRESUMO
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies.
Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Sistemas CRISPR-Cas , Fator de Transcrição Ikaros/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Citotoxicidade Celular Dependente de Anticorpos/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , HumanosRESUMO
Being the sole source of antibody, plasmablasts and plasma cells are essential for protective immunity. Due to their relative rarity, heterogeneity and the loss of many canonical B-cell markers, antibody-secreting cells (ASCs) have often been problematic to identify and further characterize. In the mouse, the combination of the expression of CD138 and BLIMP-1, has led to many insights into ASC biology, although this approach requires the use of a GFP reporter strain. In the current issue of the European Journal of Immunology, two independent studies by Wilmore et al. and Pracht et al. provide alternative approaches to identify all murine ASCs using antibodies against the cell surface proteins, Sca-1 and TACI, respectively. Here we will discuss the advantages of these new approaches to identify ASCs in the context of our emerging knowledge of the cell surface phenotype and gene expression program of various ASC subsets in the murine and human systems.
Assuntos
Células Produtoras de Anticorpos/imunologia , Plasmócitos/citologia , Animais , Linfócitos B/imunologia , Humanos , Imunoglobulinas/imunologia , Camundongos , Fatores de Transcrição/genéticaRESUMO
Follicular lymphoma (FL) is a B-cell neoplasm resulting from the transformation of germinal center (GC) B cells. Although t(14;18) and ectopic B-cell lymphoma 2 (BCL2) expression constitute the genetic hallmark of FL, t(14;18)(pos) B cells bearing genotypic and phenotypic features of FL cells can be found in the blood of most healthy individuals. Nevertheless, the localization of these FL-like cells (FLLCs) in nonmalignant GC-rich tissues and the functional consequences of BCL2 overexpression have not been evaluated thus far. Among 85 reactive lymph node (RLN) samples, 14% were found to contain high levels of t(14;18) by quantitative polymerase chain reaction. In t(14;18)(hi) RLNs, CD20(pos)BCL2(pos)CD10(pos) FLLCs consistently accumulated within the GC, essentially as nonproliferative CXCR4(neg) centrocytes. Moreover, they displayed a reduced response to proliferative stimuli in vitro. Altogether, our findings provide new insights into in situ FLLC functional properties and suggest that these cells have not acquired the ultimate genetic events leading to FL transformation.
Assuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , Linfoma de Células B/genética , Linfoma Folicular/genética , Translocação Genética , Adulto , Idoso , Antígenos CD20/genética , Antígenos CD20/metabolismo , Transformação Celular Neoplásica/genética , Feminino , Centro Germinativo/metabolismo , Centro Germinativo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neprilisina/genética , Neprilisina/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
In response to antigenic stimulation, mature B cells interact with follicular helper T cells in specialized structures called germinal centers (GCs), which leads to the development of memory B cells and Ab-secreting plasma cells. The transcription factor IFN regulatory factor 4 (IRF4) is essential for the formation of follicular helper T cells and thus GCs, although whether IRF4 plays a distinct role in GC B cells remains contentious. RNAseq analysis on ex vivo-derived mouse B cell populations showed that Irf4 was lowly expressed in naive B cells, highly expressed in plasma cells, but absent from GC B cells. In this study, we used conditional deletion of Irf4 in mature B cells as well as wild-type and Irf4-deficient mixed bone marrow chimeric mice to investigate how and where IRF4 plays its essential role in GC formation. Strikingly, GC formation was severely impaired in mice in which Irf4 was conditionally deleted in mature B cells, after immunization with protein Ags or infection with Leishmania major. This effect was evident as early as day 5 following immunization, before the development of GCs, indicating that Irf4 was required for the development of early GC B cells. This defect was B cell intrinsic because Irf4-deficient B cells in chimeric mice failed to participate in the GC in response to L. major or influenza virus infection. Taken together, these data demonstrate a B cell-intrinsic requirement for IRF4 for not only the development of Ab secreting plasma cells but also for GC formation.
Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Fatores Reguladores de Interferon/imunologia , Plasmócitos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citometria de Fluxo , Expressão Gênica/imunologia , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vírus da Influenza A Subtipo H3N2/fisiologia , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Leishmania major/imunologia , Leishmania major/fisiologia , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Plasmócitos/metabolismo , Receptores de IgE/genética , Receptores de IgE/imunologia , Receptores de IgE/metabolismo , Análise de Sequência de RNA/métodos , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
Long-term survival of plasma cells (PCs) and sustained antibody secretion require a specific microenvironment that provides the appropriate prosurvival signals. This plasma cell niche involves both mesenchymal and hematopoietic components. Although a consensus exists about the essential contribution of CXCL12(+) stromal cells in this environment, the identity of the hematopoietic participants remains a matter of debate. In this issue of the European Journal of Immunology, Zehentmeier et al. [Eur. J. Immunol. 2014. 44: 2306-2317] aim to identify the components of the bone marrow plasma cell niche in C57BL/6 mice in an unbiased manner by using a streamlined analysis of histological colocalization data. Apart from stromal cells, the authors showed that eosinophils are the only population specifically localized in the vicinity of PCs. In addition, the authors performed intravital imaging demonstrating that PCs are sessile and form stable contacts with reticular stromal cells. This work opens the door to a more rational approach to characterize the plasma cell niche.
Assuntos
Plasmócitos/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Quimiocina CXCL12/imunologia , Eosinófilos/citologia , Eosinófilos/imunologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Plasmócitos/citologia , Células Estromais/citologia , Células Estromais/imunologiaRESUMO
Regulatory T (Treg) lymphocytes play a central role in the control of autoimmune pathology. Any alteration in Treg-cell biology in mouse strains used for the study of these disorders therefore raises the question of its direct link with disease susceptibility. Paradoxically, in non-obese diabetic (NOD) mice increased numbers of Treg cells develop in the thymus. In this report we identify a locus of <7 Mbp that quantitatively controls Treg-cell development in the thymus of the NOD mouse. This 'Trd1' region is located centromeric to the H2 complex on chromosome 17 and does not include genes encoding classical MHC molecules. The genomic region identified here contains the Idd16 diabetes susceptibility locus and the use of congenic mouse strains allowed us to investigate the potential link between quantitatively altered thymic Treg cells and diabetes susceptibility. Hybrid mice present similar levels of thymic Treg cells as B6 animals but they developed diabetes with the same kinetics as NOD mice. Therefore, the increased Treg-cell development in NOD mice controlled by Trd1 is functionally dissociated from the susceptibility of NOD to diabetes.
Assuntos
Cromossomos de Mamíferos , Diabetes Mellitus/genética , Loci Gênicos , Linfócitos T Reguladores/patologia , Timo/patologia , Animais , Mapeamento Cromossômico , Diabetes Mellitus/imunologia , Diabetes Mellitus/patologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos NOD , Linfócitos T Reguladores/imunologia , Timo/imunologiaRESUMO
The germinal center (GC) reaction is critical for humoral immunity, but also contributes adversely to a variety of autoimmune diseases. While the major protective function of GCs is mediated by plasma cells and memory B cells, follicular helper T (TFH) cells represent a specialized T cell subset that provides essential help to the antigen-specific B cells in the form of membrane-bound ligands and secreted factors such as IL-21. Recent studies have revealed that TFH cells are capable of considerable functional diversity as well as possessing the ability to form memory cells. The molecular basis of this plasticity and heterogeneity is only now emerging. It has also become apparent that several other populations of follicular T cells exist, including natural killer T cells and regulatory T cells. In this review we will discuss the function of follicular T cells and interaction of these populations within the GC response.
Assuntos
Subpopulações de Linfócitos T/imunologia , Animais , Autoimunidade , Diferenciação Celular , Centro Germinativo/citologia , Centro Germinativo/imunologia , Infecções por HIV/imunologia , Humanos , Imunidade Humoral , Linfadenopatia Imunoblástica/imunologia , Interleucinas/genética , Interleucinas/metabolismo , Modelos Imunológicos , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Transcrição GênicaRESUMO
Two types of B cell in the tumor microenvironment modulate antitumor immunity.
Assuntos
Linfócitos B , Neoplasias , Microambiente Tumoral , Microambiente Tumoral/imunologia , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos B/imunologia , Animais , CamundongosRESUMO
In the bone marrow (BM), stromal cells constitute a supportive tissue indispensable for the generation of pro-B/pre-BI, pre-BII, and immature B lymphocytes. IL-7-producing stromal cells constitute a cellular niche for pro-B/pre-BI cells, but no specific stromal cell microenvironment was identified for pre-BII cells expressing a functional pre-B cell receptor (pre-BCR). However expression of the pre-BCR represents a crucial checkpoint during B-cell development. We recently demonstrated that the stromal cell derived-galectin1 (GAL1) is a ligand for the pre-BCR, involved in the proliferation and differentiation of normal mouse pre-BII cells. Here we show that nonhematopoietic osteoblasts and reticular cells in the BM express GAL1. We observed that pre-BII cells, unlike the other B-cell subsets, were specifically localized in close contact with GAL1(+) reticular cells. We also determined that IL-7(+) and GAL1(+) cells represent 2 distinct mesenchymal populations with different BM localization. These results demonstrate the existence of a pre-BII specific stromal cell niche and indicate that early B cells move from IL-7(+) to GAL1(+) supportive BM niches during their development.
Assuntos
Medula Óssea , Galectina 1/metabolismo , Células Precursoras de Linfócitos B/fisiologia , Nicho de Células-Tronco/fisiologia , Células Estromais/fisiologia , Animais , Medula Óssea/metabolismo , Medula Óssea/fisiologia , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/fisiologia , Diferenciação Celular/imunologia , Células Cultivadas , Proteínas de Fluorescência Verde/genética , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Nicho de Células-Tronco/citologia , Nicho de Células-Tronco/metabolismo , Células Estromais/citologia , Células Estromais/metabolismoRESUMO
Plasma cells (PCs) are essential for the quality and longevity of protective immunity. The canonical humoral response to vaccination involves induction of germinal centers in lymph nodes followed by maintenance by bone marrow-resident PCs, although there are many variations of this theme. Recent studies have highlighted the importance of PCs in nonlymphoid organs, including the gut, central nervous system, and skin. These sites harbor PCs with distinct isotypes and possible immunoglobulin-independent functions. Indeed, bone marrow now appears unique in housing PCs derived from multiple other organs. The mechanisms through which the bone marrow maintains PC survival long-term and the impact of their diverse origins on this process remain very active areas of research.