RESUMEN
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.
Asunto(s)
Médula Ósea , Células Plasmáticas , Células de la Médula ÓseaRESUMEN
The innate lymphoid cell (ILC) family is composed of natural killer (NK) cells, ILC1, ILC2 and ILC3, which participate in immune responses to virus, bacteria, parasites and transformed cells. ILC1, ILC2 and ILC3 subsets are mostly tissue-resident, and are profoundly imprinted by their organ of residence. They exhibit pleiotropic effects, driving seemingly paradoxical responses such as tissue repair and, alternatively, immunopathology toward allergens and promotion of tumorigenesis. Despite this, a trickle of studies now suggests that non-NK ILCs may not be overwhelmingly tumorigenic and could potentially be harnessed to drive anti-tumor responses. Here, we examine the pleiotropic behavior of ILCs in cancer and begin to unravel the gap in our knowledge that exposes a new horizon for thinking about modifying ILCs and targeting them for immunotherapy.
Asunto(s)
Inmunidad Innata , Neoplasias , Humanos , Inmunoterapia , Células Asesinas Naturales , LinfocitosRESUMEN
Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Plasticidad de la Célula/inmunología , Microambiente Celular/inmunología , Memoria Inmunológica/inmunología , Animales , Antígenos CD/inmunología , Linfocitos T CD8-positivos/citología , Femenino , Cadenas alfa de Integrinas/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
Asunto(s)
Anticuerpos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Interleucina-33/farmacología , Linfocitos/efectos de los fármacos , Melanoma Experimental/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Quimiotaxis de Leucocito/efectos de los fármacos , Citotoxicidad Inmunológica/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Eosinófilos/metabolismo , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/inmunología , Melanoma Experimental/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismoRESUMEN
Peripheral CD8+ T cell tolerance is a checkpoint in both autoimmune disease and anti-cancer immunity. Despite its importance, the relationship between tolerance-induced states and other CD8+ T cell differentiation states remains unclear. Using flow cytometric phenotyping, single-cell RNA sequencing (scRNA-seq), and chromatin accessibility profiling, we demonstrated that in vivo peripheral tolerance to a self-antigen triggered a fundamentally distinct differentiation state separate from exhaustion, memory, and functional effector cells but analogous to cells defectively primed against tumors. Tolerant cells diverged early and progressively from effector cells, adopting a transcriptionally and epigenetically distinct state within 60 h of antigen encounter. Breaching tolerance required the synergistic actions of strong T cell receptor (TCR) signaling and inflammation, which cooperatively induced gene modules that enhanced protein translation. Weak TCR signaling during bystander infection failed to breach tolerance due to the uncoupling of effector gene expression from protein translation. Thus, tolerance engages a distinct differentiation trajectory enforced by protein translation defects.
Asunto(s)
Linfocitos T CD8-positivos , Diferenciación Celular , Tolerancia Inmunológica , Biosíntesis de Proteínas , Receptores de Antígenos de Linfocitos T , Linfocitos T CD8-positivos/inmunología , Animales , Diferenciación Celular/inmunología , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Tolerancia Inmunológica/inmunología , Biosíntesis de Proteínas/inmunología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Autoantígenos/inmunologíaRESUMEN
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.
Asunto(s)
Inmunidad Mucosa/inmunología , Subgrupos Linfocitarios/inmunología , Linfocitos/inmunología , Periodicidad , Péptido Intestinal Vasoactivo/inmunología , Animales , Ingestión de Alimentos/inmunología , Inmunidad Innata/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Péptido Intestinal Vasoactivo/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Memoria Inmunológica , Malaria/inmunología , Plasmodium/inmunología , Transcriptoma , Traslado Adoptivo , Animales , Antimaláricos/farmacología , Biomarcadores , Cromatina/genética , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Malaria/parasitología , Malaria/terapia , Ratones , Plasmodium/efectos de los fármacosRESUMEN
Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-ß-signaling-dependent conversion of NK cells (CD49a-CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b-Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-ß-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.
Asunto(s)
Reprogramación Celular/inmunología , Fibrosarcoma/inmunología , Neoplasias Gastrointestinales/inmunología , Tumores del Estroma Gastrointestinal/inmunología , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/inmunología , Escape del Tumor/inmunología , Animales , Estudios de Casos y Controles , Línea Celular Tumoral , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Células Asesinas Naturales/citología , Linfocitos/citología , Linfocitos/inmunología , Ratones , Análisis de Secuencia de ARN , Transducción de Señal , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
Innate lymphoid cells (ILCs) are the most recently discovered group of immune cells. Understanding their biology poses many challenges. We discuss here the current knowledge on the appearance of ILC subsets during evolution and propose how the connection between ILCs and T cells contributes to the robustness of immunity and hence to the fitness of the hosts.
Asunto(s)
Evolución Biológica , Inmunidad Innata , Subgrupos Linfocitarios/inmunología , Linfocitos/inmunología , Linfocitos T/inmunología , Animales , Diferenciación Celular , Interacciones Huésped-Patógeno , HumanosRESUMEN
T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8(+) T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8(+) T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8(+) T cell differentiation.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Interleucina-12/inmunología , Interleucina-2/inmunología , Proteínas de Dominio T Box/inmunología , Factores de Transcripción/inmunología , Animales , Infecciones por Arenaviridae/inmunología , Inmunoprecipitación de Cromatina , Citocinas/inmunología , Citometría de Flujo , Perfilación de la Expresión Génica , Subtipo H1N1 del Virus de la Influenza A , Interleucina-17/inmunología , Virus de la Coriomeningitis Linfocítica , Ratones , Infecciones por Orthomyxoviridae/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción STAT4/inmunología , Factor de Transcripción STAT5/inmunología , Análisis de Secuencia de ARN , Transducción de SeñalRESUMEN
Intestinal T cells and group 3 innate lymphoid cells (ILC3 cells) control the composition of the microbiota and gut immune responses. Within the gut, ILC3 subsets coexist that either express or lack the natural cytoxicity receptor (NCR) NKp46. We identified here the transcriptional signature associated with the transcription factor T-bet-dependent differentiation of NCR(-) ILC3 cells into NCR(+) ILC3 cells. Contrary to the prevailing view, we found by conditional deletion of the key ILC3 genes Stat3, Il22, Tbx21 and Mcl1 that NCR(+) ILC3 cells were redundant for the control of mouse colonic infection with Citrobacter rodentium in the presence of T cells. However, NCR(+) ILC3 cells were essential for cecal homeostasis. Our data show that interplay between intestinal ILC3 cells and adaptive lymphocytes results in robust complementary failsafe mechanisms that ensure gut homeostasis.
Asunto(s)
Inmunidad Innata , Interleucinas/biosíntesis , Linfocitos/inmunología , Linfocitos/metabolismo , Animales , Citrobacter rodentium/inmunología , Análisis por Conglomerados , Modelos Animales de Enfermedad , Infecciones por Enterobacteriaceae/genética , Infecciones por Enterobacteriaceae/inmunología , Infecciones por Enterobacteriaceae/metabolismo , Infecciones por Enterobacteriaceae/mortalidad , Infecciones por Enterobacteriaceae/patología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Homeostasis , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/deficiencia , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Transducción de Señal , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Transcriptoma , Interleucina-22RESUMEN
Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.
Asunto(s)
Diferenciación Celular/inmunología , Células T Invariantes Asociadas a Mucosa/citología , Células T Invariantes Asociadas a Mucosa/fisiología , Timo/inmunología , Timo/metabolismo , Animales , Antígenos CD1d/genética , Biomarcadores , Diferenciación Celular/genética , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunofenotipificación , Células Progenitoras Linfoides/inmunología , Células Progenitoras Linfoides/metabolismo , Masculino , Ratones , Ratones Noqueados , MicroARNs/genéticaRESUMEN
The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.
Asunto(s)
Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Neoplasias/terapia , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Animales , Proliferación Celular/genética , Citotoxicidad Inmunológica/genética , Vigilancia Inmunológica , Interferón gamma/metabolismo , Interleucina-15/metabolismo , Janus Quinasa 1/metabolismo , Activación de Linfocitos/genética , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Terapia Molecular Dirigida , Neoplasias/inmunología , Transducción de Señal/genética , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.
Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos B/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , VIH/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Células Cultivadas , Regulación de la Expresión Génica , Centro Germinal/patología , Centro Germinal/virología , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Dendritic cells (DCs) are can be broadly divided into conventional (cDC) and plasmacytoid (pDC) subsets. Despite the importance of this lineage diversity, its genetic basis is not fully understood. We found that conditional ablation of the Ets-family transcription factor PU.1 in DC-restricted progenitors led to increased pDC production at the expense of cDCs. PU.1 controlled many of the cardinal functions of DCs, such as antigen presentation by cDCs and type I interferon production by pDCs. Conditional ablation of PU.1 de-repressed the pDC transcriptional signature in cDCs. The combination of genome-wide mapping of PU.1 binding and gene expression analysis revealed a key role for PU.1 in maintaining cDC identity through the induction of the transcriptional regulator DC-SCRIPT. PU.1 activated DC-SCRIPT expression, which in turn promoted cDC formation, particularly of cDC1s, and repressed pDC development. Thus, cDC identity is regulated by a transcriptional node requiring PU.1 and DC-SCRIPT.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Células Dendríticas/fisiología , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Presentación de Antígeno , Diferenciación Celular , Linaje de la Célula , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Células HEK293 , Humanos , Interferón Tipo I/metabolismo , Ratones , Ratones Transgénicos , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas/genética , Transducción de Señal , Transactivadores/genética , Factores de Transcripción/genética , TranscriptomaRESUMEN
Generation of functionally diverse effector and memory killer T cells is essential for immediate and long-term protective immunity. Herndler-Brandstetter et al. (2018) report that Bach2 promotes functional plasticity of effector T cells and the transition into the long-term memory compartment by regulating the expression of the inhibitory receptor KLRG1.