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1.
Nat Immunol ; 25(8): 1367-1382, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38992254

RESUMO

Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.


Assuntos
Apresentação de Antígeno , Autoantígenos , Linfócitos T CD8-Positivos , Inflamação , Timócitos , Timo , Animais , Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Camundongos , Timo/imunologia , Inflamação/imunologia , Apresentação de Antígeno/imunologia , Timócitos/imunologia , Timócitos/metabolismo , Camundongos Endogâmicos C57BL , Imunidade Inata , Autoimunidade/imunologia , Tolerância Imunológica/imunologia , Camundongos Transgênicos , Camundongos Knockout , Ativação Linfocitária/imunologia , Eosinófilos/imunologia
2.
Immunity ; 56(8): 1955-1974.e10, 2023 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-37490909

RESUMO

T cells differentiate into functionally distinct states upon antigen encounter. These states are delineated by different cell surface markers for murine and human T cells, which hamper cross-species translation of T cell properties. We aimed to identify surface markers that reflect the graded nature of CD8+ T cell differentiation and delineate functionally comparable states in mice and humans. CITEseq analyses revealed that graded expression of CX3CR1, encoding the chemokine receptor CX3CR1, correlated with the CD8+ T cell differentiation gradient. CX3CR1 expression distinguished human and murine CD8+ and CD4+ T cell states, as defined by migratory and functional properties. Graded CX3CR1 expression, refined with CD62L, accurately captured the high-dimensional T cell differentiation continuum. Furthermore, the CX3CR1 expression gradient delineated states with comparable properties in humans and mice in steady state and on longitudinally tracked virus-specific CD8+ T cells in both species. Thus, graded CX3CR1 expression provides a strategy to translate the behavior of distinct T cell differentiation states across species.


Assuntos
Linfócitos T CD8-Positivos , Receptores de Quimiocinas , Animais , Humanos , Camundongos , Diferenciação Celular , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/metabolismo , Memória Imunológica
3.
Immunity ; 54(10): 2169-2171, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644549

RESUMO

For new principal investigators, the first years are key to getting a laboratory off the ground and running. COVID-19 has changed the world, bringing on unforeseen difficulties and challenges at every level. We asked these investigators to share their experiences in navigating the unique environment since the start of the pandemic-what has changed in their vision for their laboratory, how they have adapted, and what advice they can share with others in a similar situation.


Assuntos
COVID-19/epidemiologia , Laboratórios , Adaptação Psicológica , Pesquisa Biomédica/tendências , COVID-19/psicologia , Comunicação , Humanos , Laboratórios/tendências , Pessoal de Laboratório/psicologia , Pessoal de Laboratório/tendências , SARS-CoV-2
4.
Cell ; 161(4): 702-4, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25957676

RESUMO

Immunization generates several memory T cell subsets that differ in their migratory properties, anatomic distribution, and, hence, accessibility to investigation. In this issue, Steinert et al. demonstrate that what was believed to be a minor memory cell subset in peripheral tissues has been dramatically underestimated. Thus, current models of protective immunity require revision.


Assuntos
Infecções por Arenaviridae/imunologia , Memória Imunológica , Vírus da Coriomeningite Linfocítica/fisiologia , Monitorização Imunológica , Subpopulações de Linfócitos T/imunologia , Animais
5.
Immunity ; 50(5): 1119-1121, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117005

RESUMO

In this issue of Immunity, van der Veeken et al. (2019) leverage genetic variation between mouse strains to assess epigenetic and transcriptional regulation dynamics in CD8+ T cells responding to acute infection.


Assuntos
Linfócitos T CD8-Positivos , Regulação da Expressão Gênica , Animais , Epigênese Genética , Epigenômica , Variação Genética , Camundongos
6.
Cell ; 154(4): 720-2, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23953106

RESUMO

Understanding the ontogeny of distinct hematopoietic cell types remains a challenge. In this issue, Schraml et al. contribute to unraveling the complexity of a central component of the mononuclear phagocyte system by using a new in vivo approach to trace the progeny of common dendritic cell precursors.


Assuntos
Linhagem da Célula , Células Dendríticas/citologia , Lectinas Tipo C/metabolismo , Receptores Imunológicos/metabolismo , Animais
7.
Eur J Immunol ; 54(1): e2350658, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37816219

RESUMO

Expression levels of the chemokine receptor CX3CR1 serve as high-resolution marker delineating functionally distinct antigen-experienced T-cell states. The factors that influence CX3CR1 expression in T cells are, however, incompletely understood. Here, we show that in vitro priming of naïve CD8+ T cells failed to robustly induce CX3CR1, which highlights the shortcomings of in vitro priming settings in recapitulating in vivo T-cell differentiation. Nevertheless, in vivo generated memory CD8+ T cells maintained CX3CR1 expression during culture. This allowed us to investigate whether T-cell receptor ligation, cell death, and CX3CL1 binding influence CX3CR1 expression. T-cell receptor stimulation led to downregulation of CX3CR1. Without stimulation, CX3CR1+ CD8+ T cells had a selective survival disadvantage, which was enhanced by factors released from necrotic but not apoptotic cells. Exposure to CX3CL1 did not rescue their survival and resulted in a dose-dependent loss of CX3CR1 surface expression. At physiological concentrations of CX3CL1, CX3CR1 surface expression was only minimally reduced, which did not hamper the interpretability of T-cell differentiation states delineated by CX3CR1. Our data further support the broad utility of CX3CR1 surface levels as T-cell differentiation marker and identify factors that influence CX3CR1 expression and the maintenance of CX3CR1 expressing CD8+ T cells.


Assuntos
Linfócitos T CD8-Positivos , Receptores de Quimiocinas , Linfócitos T CD8-Positivos/metabolismo , Receptores de Quimiocinas/genética , Microambiente Celular , Receptores de Antígenos de Linfócitos T/metabolismo , Receptor 1 de Quimiocina CX3C/metabolismo
8.
Immunity ; 45(6): 1270-1284, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27939671

RESUMO

Infections induce pathogen-specific T cell differentiation into diverse effectors (Teff) that give rise to memory (Tmem) subsets. The cell-fate decisions and lineage relationships that underlie these transitions are poorly understood. Here, we found that the chemokine receptor CX3CR1 identifies three distinct CD8+ Teff and Tmem subsets. Classical central (Tcm) and effector memory (Tem) cells and their corresponding Teff precursors were CX3CR1- and CX3CR1high, respectively. Viral infection also induced a numerically stable CX3CR1int subset that represented ∼15% of blood-borne Tmem cells. CX3CR1int Tmem cells underwent more frequent homeostatic divisions than other Tmem subsets and not only self-renewed, but also contributed to the expanding CX3CR1- Tcm pool. Both Tcm and CX3CR1int cells homed to lymph nodes, but CX3CR1int cells, and not Tem cells, predominantly surveyed peripheral tissues. As CX3CR1int Tmem cells present unique phenotypic, homeostatic, and migratory properties, we designate this subset peripheral memory (tpm) cells and propose that tpm cells are chiefly responsible for the global surveillance of non-lymphoid tissues.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Homeostase/imunologia , Vigilância Imunológica/imunologia , Receptores de Quimiocinas/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Receptor 1 de Quimiocina CX3C , Separação Celular , Citometria de Fluxo , Memória Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
9.
Eur J Immunol ; 53(3): e2250305, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36680414

RESUMO

The magnitude of CD8 T-cell responses against intracellular pathogens is thought to primarily depend on the expansion capacity of naïve T cells, given that their recruitment is considered optimal. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2023. 53: 000-000], Leube et al. challenge these concepts and show that the recruitment of naïve T-cell clones into primary responses can be far from complete. The failure to efficiently recruit T-cell clones occurs more frequently in case of low-affinity interactions of the T-cell receptor with cognate antigen of the pathogen. Using single-cell fate-mapping in the Lm-OVA model, the authors demonstrate that naïve T-cell clones of low affinity in contrast to those of high affinity often do not expand after pathogen encounter. These low-affinity clones are maintained as naïve CD8 T cells that can robustly respond upon secondary encounter with the same pathogen, in particular when the reencountered pathogen contains modifications resulting in improved recognition. Thus, this study indicates that the regulation of the response size of CD8 T cells is yet more elaborate than anticipated and involves control at the level of recruitment and expansion of naïve CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos , Receptores de Antígenos de Linfócitos T , Células Clonais , Antígenos , Diferenciação Celular
10.
Trends Immunol ; 39(3): 170-172, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29396015

RESUMO

CD8 T cells are crucial for long-term immunity. Nevertheless, the in vivo differentiation of human naïve CD8 T cells into effector and memory populations remains ill-defined. A recent study assesses the in vivo turnover of human antigen-specific CD8 T cells and suggests that long-lived memory cells arise from effector cells.


Assuntos
Óxido de Deutério , Memória Imunológica , Antígenos , Linfócitos T CD8-Positivos/citologia , Diferenciação Celular/imunologia , Humanos
11.
Scand J Immunol ; 92(6): e12983, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33037653

RESUMO

T cells responding to acute infections generally provide two key functions to protect the host: (1) active contribution to pathogen elimination and (2) providing long-lived cells that are poised to rapidly respond to renewed infection, thus ensuring long-lasting protection against the particular pathogen. Extensive work has established an astonishing amount of additional diversity among T cells actively contributing to pathogen elimination, as well as among resting, long-lived antigen-experienced T cells. This led to the description of a variety of functionally distinct T cell 'subsets'. Understanding how this heterogeneity develops among T cells responding to the same antigen is currently an active area of research, since knowledge of such mechanisms may have implications for the development of vaccines and immunotherapy. The number of naïve T cells specific to a given antigen span a great range. Considering this, one mechanistic angle focusses on how individual naïve T cells contribute to the development of the distinct T cell subsets. In this review, we highlight the current technologies that enable one to address the contributions of individual naïve T cells to different T cell subsets, with a focus on CD8 T cell subsets generated in the context of acute infections. Moreover, we discuss the requirements of new technologies to further our understanding of the mechanisms that help generate long-lasting immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Seleção Clonal Mediada por Antígeno , Imunofluorescência , Humanos , Ativação Linfocitária
12.
Immunity ; 32(6): 754-65, 2010 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-20620942

RESUMO

The adaptive immune system generates protective T cell responses via a poorly understood selection mechanism that favors expansion of clones with optimal affinity for antigen. Here we showed that upon T cell activation, the proapoptotic molecule Noxa (encoded by Pmaip1) and its antagonist Mcl-1 were induced. During an acute immune response against influenza or ovalbumin, Pmaip1(-/-) effector T cells displayed decreased antigen affinity and functionality. Molecular analysis of influenza-specific T cells revealed persistence of many subdominant clones in the Pmaip1(-/-) effector pool. When competing for low-affinity antigen, Pmaip1(-/-) TCR transgenic T cells had a survival advantage in vitro, resulting in increased numbers of effector cells in vivo. Mcl-1 protein stability was controlled by T cell receptor (TCR) affinity-dependent interleukin-2 signaling. These results establish a role for apoptosis early during T cell expansion, based on antigen-driven competition and survival of the fittest T cells.


Assuntos
Apoptose/imunologia , Ativação Linfocitária/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Separação Celular , Células Clonais , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Sequência 1 de Leucemia de Células Mieloides , Receptores de Antígenos de Linfócitos T/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia
13.
Nature ; 496(7444): 229-32, 2013 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-23552896

RESUMO

Haematopoietic stem cells (HSCs) and their subsequent progenitors produce blood cells, but the precise nature and kinetics of this production is a contentious issue. In one model, lymphoid and myeloid production branch after the lymphoid-primed multipotent progenitor (LMPP), with both branches subsequently producing dendritic cells. However, this model is based mainly on in vitro clonal assays and population-based tracking in vivo, which could miss in vivo single-cell complexity. Here we avoid these issues by using a new quantitative version of 'cellular barcoding' to trace the in vivo fate of hundreds of LMPPs and HSCs at the single-cell level. These data demonstrate that LMPPs are highly heterogeneous in the cell types that they produce, separating into combinations of lymphoid-, myeloid- and dendritic-cell-biased producers. Conversely, although we observe a known lineage bias of some HSCs, most cellular output is derived from a small number of HSCs that each generates all cell types. Crucially, in vivo analysis of the output of sibling cells derived from single LMPPs shows that they often share a similar fate, suggesting that the fate of these progenitors was imprinted. Furthermore, as this imprinting is also observed for dendritic-cell-biased LMPPs, dendritic cells may be considered a distinct lineage on the basis of separate ancestry. These data suggest a 'graded commitment' model of haematopoiesis, in which heritable and diverse lineage imprinting occurs earlier than previously thought.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula , Impressão Genômica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Animais , Código de Barras de DNA Taxonômico , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Linfócitos/citologia , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo , Células Mieloides/citologia , Células Mieloides/metabolismo , Análise de Célula Única
14.
Trends Immunol ; 35(4): 170-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24657362

RESUMO

Upon primary infection, naïve T cells that recognize their cognate antigen become activated, proliferate, and simultaneously differentiate into various subsets. A long-standing question in the field has been how this cellular diversification is achieved. Conceptually, diverse cellular output may either arise from every single cell or only from populations of naïve cells. Furthermore, such diversity may either be driven by cell-intrinsic heterogeneity or by external, niche-derived signals. In this review, we discuss how recently developed technologies have allowed the analysis of the mechanisms underlying T cell diversification at the single cell level. In addition, we outline the implications of this work on our understanding of the formation of immunological memory, and describe a number of unresolved key questions in this field.


Assuntos
Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Humanos
15.
Blood ; 119(3): 798-804, 2012 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-22128144

RESUMO

CD4(+) Th cells are pivotal for the generation and maintenance of CD8(+) T-cell responses. "Helped" CD8(+) T cells receive signals during priming that prevent the induction of the proapoptotic molecule TNF-related apoptosis-inducing ligand (TRAIL) during reactivation, thereby enabling robust secondary expansion. Conversely, "helpless" CD8(+) T cells primed in the absence of Th induce TRAIL expression after restimulation and undergo activation-induced cell death. In the present study, we investigated the molecular basis for the differential regulation of TRAIL in helped versus helpless CD8(+) T cells by comparing their transcriptional profiles, and have identified a transcriptional corepressor, NGFI-A binding protein 2 (Nab2), that is selectively induced in helped CD8(+) T cells. Enforced expression of Nab2 prevents TRAIL induction after restimulation of primary helpless CD8(+) T cells, and expression of a dominant-negative form of Nab2 in helped CD8(+) T cells impairs their secondary proliferative response that is reversible by TRAIL blockade. Finally, we observe that the CD8(+) T-cell autocrine growth factor IL-2 coordinately increases Nab2 expression and decreases TRAIL expression. These findings identify Nab2 as a mediator of Th-dependent CD8(+) T-cell memory responses through the regulation of TRAIL and the promotion of secondary expansion, and suggest a mechanism through which this operates.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-2/metabolismo , Proteínas Musculares/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Apoptose , Biomarcadores/metabolismo , Western Blotting , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Interleucina-2/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Musculares/genética , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Auxiliares-Indutores/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética
16.
Cell Rep ; 42(5): 112548, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37178121

RESUMO

Through live imaging of CD8+ T cells carrying a fate reporter, Gräbnitz et al. directly linked (a)symmetric division to T cell fate.1 Asymmetry during the first division ensured the generation of stem-like CD8+ T cells following strong T cell stimulation.


Assuntos
Divisão Celular Assimétrica , Linfócitos T CD8-Positivos , Diferenciação Celular
17.
Artigo em Inglês | MEDLINE | ID: mdl-29254978

RESUMO

Natural killer (NK) cells have historically been considered to be a part of the innate immune system, exerting a rapid response against pathogens and tumors in an antigen (Ag)-independent manner. However, over the past decade, evidence has accumulated suggesting that at least some NK cells display certain characteristics of adaptive immune cells. Indeed, NK cells can learn and remember encounters with a variety of Ags, including chemical haptens and viruses. Upon rechallenge, memory NK cells mount potent recall responses selectively to those Ags. This phenomenon, traditionally termed "immunological memory," has been reported in mice, nonhuman primates, and even humans and appears to be concentrated in discrete NK cell subsets. Because immunological memory protects against recurrent infections and is the central goal of active vaccination, it is crucial to define the mechanisms and consequences of NK cell memory. Here, we summarize the different kinds of memory responses that have been attributed to specific NK cell subsets and discuss the possibility to harness NK cell memory for vaccination purposes.


Assuntos
Memória Imunológica , Células Matadoras Naturais/fisiologia , Vacinação , Imunidade Adaptativa , Animais , Humanos , Imunidade Inata
18.
Cell Rep ; 9(4): 1375-86, 2014 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-25456132

RESUMO

To identify factors preferentially necessary for driving tumor expansion, we performed parallel in vitro and in vivo negative-selection short hairpin RNA (shRNA) screens. Melanoma cells harboring shRNAs targeting several DNA damage response (DDR) kinases had a greater selective disadvantage in vivo than in vitro, indicating an essential contribution of these factors during tumor expansion. In growing tumors, DDR kinases were activated following hypoxia. Correspondingly, depletion or pharmacologic inhibition of DDR kinases was toxic to melanoma cells, including those that were resistant to BRAF inhibitor, and this could be enhanced by angiogenesis blockade. These results reveal that hypoxia sensitizes melanomas to targeted inhibition of the DDR and illustrate the utility of in vivo shRNA dropout screens for the identification of pharmacologically tractable targets.


Assuntos
Dano ao DNA , Reparo do DNA , Testes Genéticos , Melanoma/genética , Melanoma/patologia , Interferência de RNA , Animais , Hipóxia Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Quinase do Ponto de Checagem 2/metabolismo , Reparo do DNA/efeitos dos fármacos , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Estabilidade Proteica/efeitos dos fármacos , Interferência de RNA/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Science ; 340(6132): 635-9, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23493421

RESUMO

Upon infection, antigen-specific CD8(+) T lymphocyte responses display a highly reproducible pattern of expansion and contraction that is thought to reflect a uniform behavior of individual cells. We tracked the progeny of individual mouse CD8(+) T cells by in vivo lineage tracing and demonstrated that, even for T cells bearing identical T cell receptors, both clonal expansion and differentiation patterns are heterogeneous. As a consequence, individual naïve T lymphocytes contributed differentially to short- and long-term protection, as revealed by participation of their progeny during primary versus recall infections. The discordance in fate of individual naïve T cells argues against asymmetric division as a singular driver of CD8(+) T cell heterogeneity and demonstrates that reproducibility of CD8(+) T cell responses is achieved through population averaging.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Imunidade Celular , Memória Imunológica , Listeriose/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Divisão Celular Assimétrica , Linhagem da Célula , Proliferação de Células , Imunofenotipagem , Listeria monocytogenes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Imunológicos , Receptores de Antígenos de Linfócitos T/imunologia , Análise de Célula Única , Processos Estocásticos , Subpopulações de Linfócitos T/citologia
20.
Sci Transl Med ; 4(158): 158ra145, 2012 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-23115354

RESUMO

Cell dynamics in subcutaneous and breast tumors can be studied through conventional imaging windows with intravital microscopy. By contrast, visualization of the formation of metastasis has been hampered by the lack of long-term imaging windows for metastasis-prone organs, such as the liver. We developed an abdominal imaging window (AIW) to visualize distinct biological processes in the spleen, kidney, small intestine, pancreas, and liver. The AIW can be used to visualize processes for up to 1 month, as we demonstrate with islet cell transplantation. Furthermore, we have used the AIW to image the single steps of metastasis formation in the liver over the course of 14 days. We observed that single extravasated tumor cells proliferated to form "pre-micrometastases," in which cells lacked contact with neighboring tumor cells and were active and motile within the confined region of the growing clone. The clones then condensed into micrometastases where cell migration was strongly diminished but proliferation continued. Moreover, the metastatic load was reduced by suppressing tumor cell migration in the pre-micrometastases. We suggest that tumor cell migration within pre-micrometastases is a contributing step that can be targeted therapeutically during liver metastasis formation.


Assuntos
Neoplasias Hepáticas/diagnóstico , Microscopia de Vídeo/métodos , Micrometástase de Neoplasia/diagnóstico , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos BALB C
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