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1.
Annu Rev Immunol ; 42(1): 235-258, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38271641

RESUMO

The choice of developing thymocytes to become CD8+ cytotoxic or CD4+ helper T cells has been intensely studied, but many of the underlying mechanisms remain to be elucidated. Recent multiomics approaches have provided much higher resolution analysis of gene expression in developing thymocytes than was previously achievable, thereby offering a fresh perspective on this question. Focusing on our recent studies using CITE-seq (cellular indexing of transcriptomes and epitopes) analyses of mouse thymocytes, we present a detailed timeline of RNA and protein expression changes during CD8 versus CD4 T cell differentiation. We also revisit our current understanding of the links between T cell receptor signaling and expression of the lineage-defining transcription factors ThPOK and RUNX3. Finally, we propose a sequential selection model to explain the tight linkage between MHC-I versus MHC-II recognition and T cell lineage choice. This model incorporates key aspects of previously proposed kinetic signaling, instructive, and stochastic/selection models.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Diferenciação Celular , Linhagem da Célula , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Humanos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Camundongos , Fatores de Transcrição/metabolismo , Transcriptoma , Multiômica
2.
Annu Rev Immunol ; 42(1): 347-373, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38941603

RESUMO

Plasmacytoid dendritic cells (pDCs) represent a unique cell type within the innate immune system. Their defining property is the recognition of pathogen-derived nucleic acids through endosomal Toll-like receptors and the ensuing production of type I interferon and other soluble mediators, which orchestrate innate and adaptive responses. We review several aspects of pDC biology that have recently come to the fore. We discuss emerging questions regarding the lineage affiliation and origin of pDCs and argue that these cells constitute an integral part of the dendritic cell lineage. We emphasize the specific function of pDCs as innate sentinels of virus infection, particularly their recognition of and distinct response to virus-infected cells. This essential evolutionary role of pDCs has been particularly important for the control of coronaviruses, as demonstrated by the recent COVID-19 pandemic. Finally, we highlight the key contribution of pDCs to systemic lupus erythematosus, in which therapeutic targeting of pDCs is currently underway.


Assuntos
COVID-19 , Células Dendríticas , Imunidade Inata , Lúpus Eritematoso Sistêmico , SARS-CoV-2 , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , COVID-19/imunologia , Animais , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores Toll-Like/metabolismo , Diferenciação Celular , Linhagem da Célula
3.
Annu Rev Immunol ; 40: 195-220, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35044795

RESUMO

Tissue-resident immune cells span both myeloid and lymphoid cell lineages, have been found in multiple human tissues, and play integral roles at all stages of the immune response, from maintaining homeostasis to responding to infectious challenges to resolution of inflammation to tissue repair. In humans, studying immune cells and responses in tissues is challenging, although recent advances in sampling and high-dimensional profiling have provided new insights into the ontogeny, maintenance, and functional role of tissue-resident immune cells. Each tissue contains a specific complement of resident immune cells. Moreover, resident immune cells for each lineage share core properties, along with tissue-specific adaptations. Here we propose a five-point checklist for defining resident immune cell types in humans and describe the currently known features of resident immune cells, their mechanisms of development, and their putative functional roles within various human organs. We also consider these aspects of resident immune cells in the context of future studies and therapeutics.


Assuntos
Imunidade Inata , Linfócitos , Animais , Linhagem da Célula , Homeostase , Humanos , Inflamação
4.
Annu Rev Immunol ; 39: 131-166, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33481643

RESUMO

Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity. Over the years, a variety of cell types have been called DCs on the basis of phenotypic and functional attributes. Here, we refocus attention on conventional DCs (cDCs), a discrete cell lineage by ontogenetic and gene expression criteria that best corresponds to the cells originally described in the 1970s. We summarize current knowledge of mouse and human cDC subsets and describe their hematopoietic development and their phenotypic and functional attributes. We hope that our effort to review the basic features of cDC biology and distinguish cDCs from related cell types brings to the fore the remarkable properties of this cell type while shedding some light on the seemingly inordinate complexity of the DC field.


Assuntos
Células Dendríticas , Imunidade Inata , Animais , Linhagem da Célula , Humanos , Camundongos
5.
Annu Rev Immunol ; 37: 497-519, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026413

RESUMO

During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor-invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.


Assuntos
Linfócitos B/imunologia , Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Células T Matadoras Naturais/imunologia , Timo/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Microambiente Celular , Citocinas/metabolismo , Humanos , Imunidade Inata , Ativação Linfocitária , Comunicação Parácrina , Transcriptoma
6.
Annu Rev Immunol ; 36: 579-601, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29677476

RESUMO

A fundamental question in developmental immunology is how bipotential thymocyte precursors generate both CD4+ helper and CD8+ cytotoxic T cell lineages. The MHC specificity of αß T cell receptors (TCRs) on precursors is closely correlated with cell fate-determining processes, prompting studies to characterize how variations in TCR signaling are linked with genetic programs establishing lineage-specific gene expression signatures, such as exclusive CD4 or CD8 expression. The key transcription factors ThPOK and Runx3 have been identified as mediating development of helper and cytotoxic T cell lineages, respectively. Together with increasing knowledge of epigenetic regulators, these findings have advanced our understanding of the transcription factor network regulating the CD4/CD8 dichotomy. It has also become apparent that CD4+ T cells retain developmental plasticity, allowing them to acquire cytotoxic activity in the periphery. Despite such advances, further studies are necessary to identify the molecular links between TCR signaling and the nuclear machinery regulating expression of ThPOK and Runx3.


Assuntos
Diferenciação Celular/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos CD4/genética , Antígenos CD4/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Imunomodulação/genética , Imunomodulação/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Sequências Reguladoras de Ácido Nucleico , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Fatores de Transcrição/genética , Transcrição Gênica
7.
Annu Rev Immunol ; 36: 19-42, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29144837

RESUMO

Adaptive immunity in jawless fishes is based on antigen recognition by three types of variable lymphocyte receptors (VLRs) composed of variable leucine-rich repeats, which are differentially expressed by two T-like lymphocyte lineages and one B-like lymphocyte lineage. The T-like cells express either VLRAs or VLRCs of yet undefined antigen specificity, whereas the VLRB antibodies secreted by B-like cells bind proteinaceous and carbohydrate antigens. The incomplete VLR germline genes are assembled into functional units by a gene conversion-like mechanism that employs flanking variable leucine-rich repeat sequences as templates in association with lineage-specific expression of cytidine deaminases. B-like cells develop in the hematopoietic typhlosole and kidneys, whereas T-like cells develop in the thymoid, a thymus-equivalent region at the gill fold tips. Thus, the dichotomy between T-like and B-like cells and the presence of dedicated lymphopoietic tissues emerge as ancestral vertebrate features, whereas the somatic diversification of structurally distinct antigen receptor genes evolved independently in jawless and jawed vertebrates.


Assuntos
Imunidade Adaptativa , Evolução Biológica , Vertebrados/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem da Célula , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Humanos , Imunidade Inata , Família Multigênica , Receptores de Antígenos de Linfócitos B/química , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vertebrados/metabolismo
8.
Cell ; 187(19): 5298-5315.e19, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39168124

RESUMO

During wound healing, different pools of stem cells (SCs) contribute to skin repair. However, how SCs become activated and drive the tissue remodeling essential for skin repair is still poorly understood. Here, by developing a mouse model allowing lineage tracing and basal cell lineage ablation, we monitor SC fate and tissue dynamics during regeneration using confocal and intravital imaging. Analysis of basal cell rearrangements shows dynamic transitions from a solid-like homeostatic state to a fluid-like state allowing tissue remodeling during repair, as predicted by a minimal mathematical modeling of the spatiotemporal dynamics and fate behavior of basal cells. The basal cell layer progressively returns to a solid-like state with re-epithelialization. Bulk, single-cell RNA, and epigenetic profiling of SCs, together with functional experiments, uncover a common regenerative state regulated by the EGFR/AP1 axis activated during tissue fluidization that is essential for skin SC activation and tissue repair.


Assuntos
Pele , Cicatrização , Animais , Camundongos , Pele/metabolismo , Receptores ErbB/metabolismo , Células-Tronco/metabolismo , Células-Tronco/citologia , Linhagem da Célula , Regeneração , Camundongos Endogâmicos C57BL , Reepitelização , Diferenciação Celular , Queratinócitos/metabolismo , Queratinócitos/citologia
9.
Cell ; 187(12): 2919-2934.e20, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38761800

RESUMO

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.


Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Linfócitos B , Anticorpos Anti-HIV , HIV-1 , Humanos , Vacinas contra a AIDS/imunologia , HIV-1/imunologia , Anticorpos Neutralizantes/imunologia , Linfócitos B/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Linhagem da Célula , Lipossomos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Mutação , Proteína gp41 do Envelope de HIV/imunologia
10.
Cell ; 187(12): 3039-3055.e14, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38848677

RESUMO

In the prevailing model, Lgr5+ cells are the only intestinal stem cells (ISCs) that sustain homeostatic epithelial regeneration by upward migration of progeny through elusive upper crypt transit-amplifying (TA) intermediates. Here, we identify a proliferative upper crypt population marked by Fgfbp1, in the location of putative TA cells, that is transcriptionally distinct from Lgr5+ cells. Using a kinetic reporter for time-resolved fate mapping and Fgfbp1-CreERT2 lineage tracing, we establish that Fgfbp1+ cells are multi-potent and give rise to Lgr5+ cells, consistent with their ISC function. Fgfbp1+ cells also sustain epithelial regeneration following Lgr5+ cell depletion. We demonstrate that FGFBP1, produced by the upper crypt cells, is an essential factor for crypt proliferation and epithelial homeostasis. Our findings support a model in which tissue regeneration originates from upper crypt Fgfbp1+ cells that generate progeny propagating bi-directionally along the crypt-villus axis and serve as a source of Lgr5+ cells in the crypt base.


Assuntos
Mucosa Intestinal , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/metabolismo , Animais , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Linhagem da Célula , Regeneração , Proliferação de Células , Células Epiteliais/metabolismo , Células Epiteliais/citologia , Camundongos Endogâmicos C57BL , Homeostase
11.
Cell ; 187(11): 2855-2874.e19, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38657603

RESUMO

Progress in understanding early human development has been impeded by the scarcity of reference datasets from natural embryos, particularly those with spatial information during crucial stages like gastrulation. We conducted high-resolution spatial transcriptomics profiling on 38,562 spots from 62 transverse sections of an intact Carnegie stage (CS) 8 human embryo. From this spatial transcriptomic dataset, we constructed a 3D model of the CS8 embryo, in which a range of cell subtypes are identified, based on gene expression patterns and positional register, along the anterior-posterior, medial-lateral, and dorsal-ventral axis in the embryo. We further characterized the lineage trajectories of embryonic and extra-embryonic tissues and associated regulons and the regionalization of signaling centers and signaling activities that underpin lineage progression and tissue patterning during gastrulation. Collectively, the findings of this study provide insights into gastrulation and post-gastrulation development of the human embryo.


Assuntos
Embrião de Mamíferos , Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Imageamento Tridimensional , Humanos , Embrião de Mamíferos/metabolismo , Transcriptoma/genética , Gástrula/metabolismo , Gástrula/embriologia , Transdução de Sinais , Linhagem da Célula , Perfilação da Expressão Gênica , Padronização Corporal/genética
12.
Cell ; 187(11): 2838-2854.e17, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38744282

RESUMO

Retrospective lineage reconstruction of humans predicts that dramatic clonal imbalances in the body can be traced to the 2-cell stage embryo. However, whether and how such clonal asymmetries arise in the embryo is unclear. Here, we performed prospective lineage tracing of human embryos using live imaging, non-invasive cell labeling, and computational predictions to determine the contribution of each 2-cell stage blastomere to the epiblast (body), hypoblast (yolk sac), and trophectoderm (placenta). We show that the majority of epiblast cells originate from only one blastomere of the 2-cell stage embryo. We observe that only one to three cells become internalized at the 8-to-16-cell stage transition. Moreover, these internalized cells are more frequently derived from the first cell to divide at the 2-cell stage. We propose that cell division dynamics and a cell internalization bottleneck in the early embryo establish asymmetry in the clonal composition of the future human body.


Assuntos
Blastômeros , Linhagem da Célula , Embrião de Mamíferos , Feminino , Humanos , Blastômeros/citologia , Blastômeros/metabolismo , Divisão Celular , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário , Camadas Germinativas/citologia , Camadas Germinativas/metabolismo , Masculino , Animais , Camundongos
13.
Cell ; 187(10): 2428-2445.e20, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38579712

RESUMO

Alveolar type 2 (AT2) cells are stem cells of the alveolar epithelia. Previous genetic lineage tracing studies reported multiple cellular origins for AT2 cells after injury. However, conventional lineage tracing based on Cre-loxP has the limitation of non-specific labeling. Here, we introduced a dual recombinase-mediated intersectional genetic lineage tracing approach, enabling precise investigation of AT2 cellular origins during lung homeostasis, injury, and repair. We found AT1 cells, being terminally differentiated, did not contribute to AT2 cells after lung injury and repair. Distinctive yet simultaneous labeling of club cells, bronchioalveolar stem cells (BASCs), and existing AT2 cells revealed the exact contribution of each to AT2 cells post-injury. Mechanistically, Notch signaling inhibition promotes BASCs but impairs club cells' ability to generate AT2 cells during lung repair. This intersectional genetic lineage tracing strategy with enhanced precision allowed us to elucidate the physiological role of various epithelial cell types in alveolar regeneration following injury.


Assuntos
Células Epiteliais Alveolares , Pulmão , Células-Tronco , Animais , Camundongos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/citologia , Diferenciação Celular , Linhagem da Célula , Pulmão/citologia , Pulmão/metabolismo , Pulmão/fisiologia , Lesão Pulmonar/patologia , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Receptores Notch/metabolismo , Regeneração , Transdução de Sinais , Células-Tronco/metabolismo , Células-Tronco/citologia
14.
Cell ; 187(15): 4010-4029.e16, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38917790

RESUMO

Mammalian blastocyst formation involves the specification of the trophectoderm followed by the differentiation of the inner cell mass into embryonic epiblast and extra-embryonic primitive endoderm (PrE). During this time, the embryo maintains a window of plasticity and can redirect its cellular fate when challenged experimentally. In this context, we found that the PrE alone was sufficient to regenerate a complete blastocyst and continue post-implantation development. We identify an in vitro population similar to the early PrE in vivo that exhibits the same embryonic and extra-embryonic potency and can form complete stem cell-based embryo models, termed blastoids. Commitment in the PrE is suppressed by JAK/STAT signaling, collaborating with OCT4 and the sustained expression of a subset of pluripotency-related transcription factors that safeguard an enhancer landscape permissive for multi-lineage differentiation. Our observations support the notion that transcription factor persistence underlies plasticity in regulative development and highlight the importance of the PrE in perturbed development.


Assuntos
Blastocisto , Diferenciação Celular , Endoderma , Animais , Endoderma/metabolismo , Endoderma/citologia , Camundongos , Blastocisto/metabolismo , Blastocisto/citologia , Linhagem da Célula , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Transdução de Sinais , Desenvolvimento Embrionário , Janus Quinases/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição STAT/metabolismo , Fatores de Transcrição/metabolismo , Feminino , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/citologia
15.
Cell ; 187(11): 2817-2837.e31, 2024 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-38701783

RESUMO

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG, is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells.


Assuntos
Células Matadoras Naturais , Proteínas de Membrana , Animais , Feminino , Humanos , Masculino , Camundongos , Linfócitos B/metabolismo , Linfócitos B/citologia , Medula Óssea/metabolismo , Linhagem da Célula , Células Dendríticas/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia , Células de Langerhans/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Monócitos/metabolismo , Pele/metabolismo , Camundongos Endogâmicos C57BL
16.
Cell ; 187(13): 3284-3302.e23, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38843832

RESUMO

The cleavage of zygotes generates totipotent blastomeres. In human 8-cell blastomeres, zygotic genome activation (ZGA) occurs to initiate the ontogenesis program. However, capturing and maintaining totipotency in human cells pose significant challenges. Here, we realize culturing human totipotent blastomere-like cells (hTBLCs). We find that splicing inhibition can transiently reprogram human pluripotent stem cells into ZGA-like cells (ZLCs), which subsequently transition into stable hTBLCs after long-term passaging. Distinct from reported 8-cell-like cells (8CLCs), both ZLCs and hTBLCs widely silence pluripotent genes. Interestingly, ZLCs activate a particular group of ZGA-specific genes, and hTBLCs are enriched with pre-ZGA-specific genes. During spontaneous differentiation, hTBLCs re-enter the intermediate ZLC stage and further generate epiblast (EPI)-, primitive endoderm (PrE)-, and trophectoderm (TE)-like lineages, effectively recapitulating human pre-implantation development. Possessing both embryonic and extraembryonic developmental potency, hTBLCs can autonomously generate blastocyst-like structures in vitro without external cell signaling. In summary, our study provides key criteria and insights into human cell totipotency.


Assuntos
Diferenciação Celular , Spliceossomos , Animais , Humanos , Camundongos , Blastocisto/metabolismo , Blastocisto/citologia , Blastômeros/metabolismo , Blastômeros/citologia , Reprogramação Celular , Desenvolvimento Embrionário/genética , Camadas Germinativas/metabolismo , Camadas Germinativas/citologia , Células-Tronco Pluripotentes/metabolismo , Células-Tronco Pluripotentes/citologia , Splicing de RNA , Spliceossomos/metabolismo , Células-Tronco Totipotentes/metabolismo , Células-Tronco Totipotentes/citologia , Zigoto/metabolismo , Células Cultivadas , Modelos Moleculares , Estrutura Terciária de Proteína , Genoma Humano , Análise de Célula Única , Fator 15 de Diferenciação de Crescimento/química , Fator 15 de Diferenciação de Crescimento/genética , Fator 15 de Diferenciação de Crescimento/metabolismo , Epigenômica , Linhagem da Célula
17.
Annu Rev Immunol ; 34: 93-119, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-26735697

RESUMO

The dendritic cells (DCs) of the immune system function in innate and adaptive responses by directing activity of various effector cells rather than serving as effectors themselves. DCs and closely related myeloid lineages share expression of many surface receptors, presenting a challenge in distinguishing their unique in vivo functions. Recent work has taken advantage of unique transcriptional programs to identify and manipulate murine DCs in vivo. This work has assigned several nonredundant in vivo functions to distinct DC lineages, consisting of plasmacytoid DCs and several subsets of classical DCs that promote different immune effector modules in response to pathogens. In parallel, a correspondence between human and murine DC subsets has emerged, underlying structural similarities for the DC lineages between these species. Recent work has begun to unravel the transcriptional circuitry that controls the development and diversification of DCs from common progenitors in the bone marrow.


Assuntos
Células da Medula Óssea/fisiologia , Células Dendríticas/fisiologia , Regulação da Expressão Gênica , Imunidade Celular , Animais , Diferenciação Celular , Linhagem da Célula , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imunidade Celular/genética , Camundongos , Ativação Transcricional
18.
Annu Rev Immunol ; 34: 449-78, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27168243

RESUMO

Hematopoietic stem cells (HSCs) and downstream progenitors have long been studied based on phenotype, cell purification, proliferation, and transplantation into myeloablated recipients. These experiments, complemented by data on expression profiles, mouse mutants, and humans with hematopoietic defects, are the foundation for the current hematopoietic differentiation tree. However, there are fundamental gaps in our knowledge of the quantitative and qualitative operation of the HSC/progenitor system under physiological and pathological conditions in vivo. The hallmarks of HSCs, self-renewal and multipotency, are observed in in vitro assays and cell transplantation experiments; however, the extent to which these features occur naturally in HSCs and progenitors remains uncertain. We focus here on work that strives to address these unresolved questions, with emphasis on fate mapping and modeling of the hematopoietic flow from stem cells toward myeloid and lymphoid lineages during development and adult life.


Assuntos
Envelhecimento/imunologia , Diferenciação Celular , Hematopoese , Células-Tronco Hematopoéticas/fisiologia , Células Progenitoras Linfoides/fisiologia , Animais , Linhagem da Célula , Autorrenovação Celular , Humanos , Camundongos , Modelos Teóricos , Transcriptoma
19.
Annu Rev Immunol ; 34: 65-92, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-26666651

RESUMO

T cell responses display two key characteristics. First, a small population of epitope-specific naive T cells expands by several orders of magnitude. Second, the T cells within this proliferating population take on diverse functional and phenotypic properties that determine their ability to exert effector functions and contribute to T cell memory. Recent technological advances in lineage tracing allow us for the first time to study these processes in vivo at single-cell resolution. Here, we summarize resulting data demonstrating that although epitope-specific T cell responses are reproducibly similar at the population level, expansion potential and diversification patterns of the offspring derived from individual T cells are highly variable during both primary and recall immune responses. In spite of this stochastic response variation, individual memory T cells can serve as adult stem cells that provide robust regeneration of an epitope-specific tissue through population averaging. We discuss the relevance of these findings for T cell memory formation and clinical immunotherapy.


Assuntos
Células-Tronco Adultas/imunologia , Diferenciação Celular , Imunoterapia/métodos , Análise de Célula Única/métodos , Linfócitos T/imunologia , Animais , Biodiversidade , Linhagem da Célula , Proliferação de Células , Diversidade Cultural , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/metabolismo , Humanos , Memória Imunológica , Ativação Linfocitária
20.
Annu Rev Immunol ; 34: 299-316, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-27168240

RESUMO

The discovery of tissue-resident innate lymphoid cell populations effecting different forms of type 1, 2, and 3 immunity; tissue repair; and immune regulation has transformed our understanding of mucosal immunity and allergy. The emerging complexity of these populations along with compounding issues of redundancy and plasticity raise intriguing questions about their precise lineage relationship. Here we review advances in mapping the emergence of these lineages from early lymphoid precursors. We discuss the identification of a common innate lymphoid cell precursor characterized by transient expression of the transcription factor PLZF, and the lineage relationships of innate lymphoid cells with conventional natural killer cells and lymphoid tissue inducer cells. We also review the rapidly growing understanding of the network of transcription factors that direct the development of these lineages.


Assuntos
Diferenciação Celular , Hipersensibilidade/imunologia , Imunidade Inata , Linfócitos/imunologia , Células Progenitoras Linfoides/imunologia , Animais , Linhagem da Célula , Citocinas/metabolismo , Regulação da Expressão Gênica/imunologia , Redes Reguladoras de Genes , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica , Células Th1/imunologia , Células Th2/imunologia
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