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2.
Trends Immunol ; 40(1): 35-48, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502023

RESUMO

Subcapsular sinus (SCS) macrophages are strategically positioned at the lymph-tissue interface in the lymph node to trap and present antigen to B cells. Recent murine data has shown that SCS macrophages also prevent the systemic spread of lymph-borne pathogens and are capable of activating a diverse range of innate effector and adaptive memory cells, including follicular memory T cells and memory B cells (Bmems), that are either pre-positioned or rapidly recruited to the subcapsular niche following infection and inflammation. Furthermore, Bmems are rapidly reactivated to differentiate into plasma cells in subcapsular proliferative foci (SPF). Thus, understanding how SCS macrophages coordinate both innate and adaptive memory responses in the subcapsular niche can provide new opportunities to bolster immunity against pathogens and cancer.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Linfonodos/imunologia , Macrófagos/imunologia , Animais , Camundongos
3.
Nat Commun ; 9(1): 3372, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135429

RESUMO

Vaccine-induced immunity depends on the generation of memory B cells (MBC). However, where and how MBCs are reactivated to make neutralising antibodies remain unknown. Here we show that MBCs are prepositioned in a subcapsular niche in lymph nodes where, upon reactivation by antigen, they rapidly proliferate and differentiate into antibody-secreting plasma cells in the subcapsular proliferative foci (SPF). This novel structure is enriched for signals provided by T follicular helper cells and antigen-presenting subcapsular sinus macrophages. Compared with contemporaneous secondary germinal centres, SPF have distinct single-cell molecular signature, cell migration pattern and plasma cell output. Moreover, SPF are found both in human and mouse lymph nodes, suggesting that they are conserved throughout mammalian evolution. Our data thus reveal that SPF is a seat of immunological memory that may be exploited to rapidly mobilise secondary antibody responses and improve vaccine efficacy.


Assuntos
Linfócitos B/metabolismo , Linfonodos/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Humanos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Tamoxifeno/farmacologia
4.
Front Immunol ; 9: 1553, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022984

RESUMO

Single-cell RNA sequencing (scRNA-Seq) is transforming our ability to characterize cells, particularly rare cells that are often overlooked in bulk population analytical approaches. This has lead to the discovery of new cell types and cellular states that echo the underlying heterogeneity and plasticity in the immune system. Technologies for the capture, sequencing, and bioinformatic analysis of single cells are rapidly improving, and scRNA-Seq is now becoming much more accessible to non-specialized laboratories. Here, we describe our experiences in adopting scRNA-Seq to the study of rare immune cells in their microanatomical niches.

5.
Elife ; 72018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985127

RESUMO

Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark Galene, a versatile multi-platform software tool for image-based correction of sample motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that Galene is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, Galene can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.


Assuntos
Imagem Tridimensional , Microscopia Intravital , Movimento (Física) , Algoritmos , Animais , Técnicas Biossensoriais , Adesão Celular , Simulação por Computador , Transferência Ressonante de Energia de Fluorescência , Guanosina Trifosfato/metabolismo , Humanos , Intestinos/fisiologia , Camundongos , Microscopia de Fluorescência , Modelos Biológicos , Metástase Neoplásica , Neuropeptídeos/metabolismo , Neoplasias Pancreáticas/patologia , Pele/anatomia & histologia , Software , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases da Família src/metabolismo
6.
Immunol Rev ; 283(1): 138-149, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29664566

RESUMO

The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells act as a first line of defense against reinfection ("constitutive humoral memory"). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies ("reactive humoral memory"), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). However, in the case of re-infection with similar but different strains of viruses, or in response to viral escape mutants, the reactive humoral memory plays a crucial role. Here, we review recent progress in our understanding of how memory B cells are generated in the pre-GC stage and during the GC reaction, and how these memory B cells are robustly reactivated with the help of memory Tfh cells to generate the secondary antibody response. In addition, we discuss how these advances may be relevant to the quest for a vaccine that can induce broadly reactive antibodies against influenza and HIV.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Imunidade Humoral , Memória Imunológica , Ativação Linfocitária/imunologia , Animais , Formação de Anticorpos/imunologia , Humanos , Vacinas/imunologia , Viroses/imunologia , Vírus/imunologia
7.
Methods Mol Biol ; 1623: 59-72, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28589347

RESUMO

The germinal center (GC) reaction is the key process for the generation of high affinity antibodies to foreign antigen. Standard experimental techniques such as fluorescence-activated cell sorting and histology have provided numerous insights into the composition and function of the GC. However, these approaches are limited to a "snapshot" in time and are unable to fully capture the dynamic nature of the GC. Intravital two-photon microscopy overcomes these disadvantages and has led to several major advances in the field but is restricted by practical and technical limits that prevent long-range mapping and molecular studies. Here we describe procedures for optical marking or "tagging" of cells in precise microanatomical compartments by two-photon photoconversion that can be used for long-term fate mapping and transcript profiling of GC T and B cells.


Assuntos
Perfilação da Expressão Gênica , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Microscopia , Imagem Molecular , Animais , Biomarcadores , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica/métodos , Centro Germinativo/imunologia , Processamento de Imagem Assistida por Computador , Imunização , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia/métodos , Imagem Molecular/métodos
8.
Immunity ; 42(4): 704-18, 2015 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-25840682

RESUMO

B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169(+) subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen-experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen.


Assuntos
Linfócitos B/citologia , Linhagem da Célula/imunologia , Centro Germinativo/citologia , Imunidade Humoral , Linfócitos T Auxiliares-Indutores/citologia , Animais , Linfócitos B/imunologia , Diferenciação Celular , Linhagem da Célula/genética , Movimento Celular/imunologia , Proliferação de Células , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Centro Germinativo/imunologia , Memória Imunológica , Camundongos , Camundongos Knockout , Cultura Primária de Células , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 1 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia
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