RESUMEN
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.
Asunto(s)
Diferenciación Celular , Hipersensibilidad/inmunología , Inmunidad Innata , Linfocitos/inmunología , Células Progenitoras Linfoides/inmunología , Animales , Linaje de la Célula , Citocinas/metabolismo , Regulación de la Expresión Génica/inmunología , Redes Reguladoras de Genes , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.
Asunto(s)
Neoplasias , Linfocitos T Reguladores , Animales , Ratones , Humanos , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Microambiente Tumoral , Neoplasias/metabolismoRESUMEN
Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.
Asunto(s)
Diferenciación Celular/genética , Linaje de la Célula/genética , Heterogeneidad Genética , Neoplasias/inmunología , Inmunidad Adaptativa/genética , Animales , Diferenciación Celular/inmunología , Cromatina/genética , Células Dendríticas/inmunología , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunidad Innata/genética , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Ratones , Neoplasias/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transcripción Genética/inmunologíaRESUMEN
Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD. VIDEO ABSTRACT.
Asunto(s)
Enfermedad Celíaca/inmunología , Inflamación/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Antígenos , Butirofilinas/metabolismo , Enfermedad Celíaca/fisiopatología , Enfermedad Crónica , Dieta Sin Gluten , Glútenes/metabolismo , Células HEK293 , Humanos , Inflamación/metabolismo , Mucosa Intestinal/inmunología , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismoRESUMEN
The precise lineage relationship between innate lymphoid cells (ILCs) and lymphoid tissue-inducer (LTi) cells is poorly understood. Using single-cell multiplex transcriptional analysis of 100 lymphoid genes and single-cell cultures of fetal liver precursor cells, we identified the common proximal precursor to these lineages and found that its bifurcation was marked by differential induction of the transcription factors PLZF and TCF1. Acquisition of individual effector programs specific to the ILC subsets ILC1, ILC2 and ILC3 was initiated later, at the common ILC precursor stage, by transient expression of mixed ILC1, ILC2 and ILC3 transcriptional patterns, whereas, in contrast, the development of LTi cells did not go through multilineage priming. Our findings provide insight into the divergent mechanisms of the differentiation of the ILC lineage and LTi cell lineage and establish a high-resolution 'blueprint' of their development.
Asunto(s)
Linaje de la Célula/inmunología , Subgrupos Linfocitarios/inmunología , Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular/genética , Citometría de Flujo , Perfilación de la Expresión Génica , Factor Nuclear 1-alfa del Hepatocito/inmunología , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/inmunología , Tejido Linfoide/citología , Ratones , Reacción en Cadena de la Polimerasa Multiplex , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de la Célula IndividualRESUMEN
Among the variety of tissue-resident NK-like populations recently distinguished from recirculating classical NK (cNK) cells, liver innate lymphoid cells (ILC) type 1 (ILC1s) have been shown to represent a distinct lineage that originates from a novel promyelocytic leukaemia zinc finger (PLZF)-expressing ILC precursor (ILCP) strictly committed to the ILC1, ILC2, and ILC3 lineages. Here, using PLZF-reporter mice and cell transfer assays, we studied the developmental progression of ILC1s and demonstrated substantial overlap with stages previously ascribed to the cNK lineage, including pre-pro-NK, pre-NK precursor (pre-NKP), refined NKP (rNKP), and immature NK (iNK). Although they originated from different precursors, the ILC1 and cNK lineages followed a parallel progression at early stages and diverged later at the iNK stage, with a striking predominance of ILC1s over cNKs early in ontogeny. Although a limited set of ILC1 genes depended on PLZF for expression, characteristically including Il7r, most of these genes were also differentially expressed between ILC1s and cNKs, indicating that PLZF together with other, yet to be defined, factors contribute to the divergence between these lineages.
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Linaje de la Célula , Inmunidad Innata , Factores de Transcripción de Tipo Kruppel/metabolismo , Linfocitos/citología , Linfocitos/metabolismo , Animales , Animales Recién Nacidos , Antígenos Ly/metabolismo , Células de la Médula Ósea/citología , Diferenciación Celular/genética , Linaje de la Célula/genética , Feto/citología , Perfilación de la Expresión Génica , Inmunidad Innata/genética , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Hígado/citología , Hígado/embriología , Ratones Endogámicos C57BL , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Células Madre/citología , Células Madre/inmunologíaRESUMEN
Many experimental systems consist of large ensembles of uncoupled or weakly interacting elements operating as a single whole; this is particularly the case for applications in nano-optics and plasmonics, including colloidal solutions, plasmonic or dielectric nanoparticles on a substrate, antenna arrays, and others. In such experiments, measurements of the optical spectra of ensembles will differ from measurements of the independent elements as a result of small variations from element to element (also known as polydispersity) even if these elements are designed to be identical. In particular, sharp spectral features arising from narrow-band resonances will tend to appear broader and can even be washed out completely. Here, we explore this effect of inhomogeneous broadening as it occurs in colloidal nanopolymers comprising self-assembled nanorod chains in solution. Using a technique combining finite-difference time-domain simulations and Monte Carlo sampling, we predict the inhomogeneously broadened optical spectra of these colloidal nanopolymers and observe significant qualitative differences compared with the unbroadened spectra. The approach combining an electromagnetic simulation technique with Monte Carlo sampling is widely applicable for quantifying the effects of inhomogeneous broadening in a variety of physical systems, including those with many degrees of freedom that are otherwise computationally intractable.
RESUMEN
Robust methods for identifying patterns of expression in genome-wide data are important for generating hypotheses regarding gene function. To this end, several analytic methods have been developed for detecting periodic patterns. We improve one such method, JTK_CYCLE, by explicitly calculating the null distribution such that it accounts for multiple hypothesis testing and by including non-sinusoidal reference waveforms. We term this method empirical JTK_CYCLE with asymmetry search, and we compare its performance to JTK_CYCLE with Bonferroni and Benjamini-Hochberg multiple hypothesis testing correction, as well as to five other methods: cyclohedron test, address reduction, stable persistence, ANOVA, and F24. We find that ANOVA, F24, and JTK_CYCLE consistently outperform the other three methods when data are limited and noisy; empirical JTK_CYCLE with asymmetry search gives the greatest sensitivity while controlling for the false discovery rate. Our analysis also provides insight into experimental design and we find that, for a fixed number of samples, better sensitivity and specificity are achieved with higher numbers of replicates than with higher sampling density. Application of the methods to detecting circadian rhythms in a metadataset of microarrays that quantify time-dependent gene expression in whole heads of Drosophila melanogaster reveals annotations that are enriched among genes with highly asymmetric waveforms. These include a wide range of oxidation reduction and metabolic genes, as well as genes with transcripts that have multiple splice forms.
Asunto(s)
Ritmo Circadiano/genética , Perfilación de la Expresión Génica/métodos , Genómica/métodos , Modelos Genéticos , Modelos Estadísticos , Animales , Simulación por Computador , Drosophila melanogaster/genética , Genoma de los Insectos/genéticaRESUMEN
B cells are unique antigen-presenting cells because their antigen presentation machinery is closely tied to the B cell receptor. Autoreactive thymic B cells can efficiently present cognate self-antigens to mediate CD4+ T cell-negative selection. However, the nature of thymocyte-thymic B cell interaction and how this interaction affects the selection of thymic B cell repertoire and, in turn, the T cell repertoire are not well understood. Here we demonstrate that a large percentage of thymic B cells have undergone class switching intrathymically. Thymic B cell class switching requires cognate interaction with specific T cells. Class-switched thymic B cells have a distinct repertoire compared with unswitched thymic B cells or splenic B cells. Particularly, autoreactive B cell specificities preferentially expand in the thymus by undergoing class switching, and these enriched, class-switched autoreactive thymic B cells play an important role in CD4 T cell tolerance.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos B/inmunología , Tolerancia Central/inmunología , Cambio de Clase de Inmunoglobulina/inmunología , Linfocitos T/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Autoantígenos/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Humanos , Activación de Linfocitos/inmunología , Ratones , Timocitos/inmunología , Timocitos/metabolismoRESUMEN
Yan is an ETS-domain transcription factor responsible for maintaining Drosophila eye cells in a multipotent state. Yan is at the core of a regulatory network that determines the time and place in which cells transit from multipotency to one of several differentiated lineages. Using a fluorescent reporter for Yan expression, we observed a biphasic distribution of Yan in multipotent cells, with a rapid inductive phase and slow decay phase. Transitions to various differentiated states occurred over the course of this dynamic process, suggesting that Yan expression level does not strongly determine cell potential. Consistent with this conclusion, perturbing Yan expression by varying gene dosage had no effect on cell fate transitions. However, we observed that as cells transited to differentiation, Yan expression became highly heterogeneous and this heterogeneity was transient. Signals received via the EGF Receptor were necessary for the transience in Yan noise since genetic loss caused sustained noise. Since these signals are essential for eye cells to differentiate, we suggest that dynamic heterogeneity of Yan is a necessary element of the transition process, and cell states are stabilized through noise reduction.