RESUMEN
Natural killer (NK) cells are innate lymphocytes that provide critical host defense against pathogens and cancer. Originally heralded for their early and rapid effector activity, NK cells have been recognized over the last decade for their ability to undergo adaptive immune processes, including antigen-driven clonal expansion and generation of long-lived memory. This review presents an overview of how NK cells lithely partake in both innate and adaptive responses and how this versatility is manifest in human NK cell-mediated immunity.
Asunto(s)
Infecciones por Citomegalovirus , Citomegalovirus , Animales , Humanos , Inmunidad Celular , Células Asesinas NaturalesRESUMEN
Natural killer (NK) cells function by eliminating virus-infected or tumor cells. Here we identified an NK-lineage-biased progenitor population, referred to as early NK progenitors (ENKPs), which developed into NK cells independently of common precursors for innate lymphoid cells (ILCPs). ENKP-derived NK cells (ENKP_NK cells) and ILCP-derived NK cells (ILCP_NK cells) were transcriptionally different. We devised combinations of surface markers that identified highly enriched ENKP_NK and ILCP_NK cell populations in wild-type mice. Furthermore, Ly49H+ NK cells that responded to mouse cytomegalovirus infection primarily developed from ENKPs, whereas ILCP_NK cells were better IFNγ producers after infection with Salmonella and herpes simplex virus. Human CD56dim and CD56bright NK cells were transcriptionally similar to ENKP_NK cells and ILCP_NK cells, respectively. Our findings establish the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice and further suggest these pathways may be conserved in humans.
Asunto(s)
Diferenciación Celular , Células Asesinas Naturales , Células Asesinas Naturales/inmunología , Animales , Ratones , Humanos , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Inmunidad Innata , Antígeno CD56/metabolismo , Muromegalovirus/inmunología , Linaje de la Célula/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/inmunología , Ratones Noqueados , Células CultivadasRESUMEN
The ability of vertebrates to 'remember' previous infections had once been attributed exclusively to adaptive immunity. We now appreciate that innate lymphocytes also possess memory properties akin to those of adaptive immune cells. In this Review, we draw parallels from T cell biology to explore the key features of immune memory in innate lymphocytes, including quantity, quality, and location. We discuss the signals that trigger clonal or clonal-like expansion in innate lymphocytes, and highlight recent studies that shed light on the complex cellular and molecular crosstalk between metabolism, epigenetics, and transcription responsible for differentiating innate lymphocyte responses towards a memory fate. Additionally, we explore emerging evidence that activated innate lymphocytes relocate and establish themselves in specific peripheral tissues during infection, which may facilitate an accelerated response program akin to those of tissue-resident memory T cells.
Asunto(s)
Inmunidad Innata , Memoria Inmunológica , Animales , Linfocitos , Inmunidad Adaptativa , Células ClonalesRESUMEN
Natural killer (NK) cells are innate cytotoxic lymphocytes with adaptive immune features, including antigen specificity, clonal expansion and memory. As such, NK cells share many transcriptional and epigenetic programs with their adaptive CD8+ T cell siblings. Various signals ranging from antigen, co-stimulation and proinflammatory cytokines are required for optimal NK cell responses in mice and humans during virus infection; however, the integration of these signals remains unclear. In this study, we identified that the transcription factor IRF4 integrates signals to coordinate the NK cell response during mouse cytomegalovirus infection. Loss of IRF4 was detrimental to the expansion and differentiation of virus-specific NK cells. This defect was partially attributed to the inability of IRF4-deficient NK cells to uptake nutrients required for survival and memory generation. Altogether, these data suggest that IRF4 is a signal integrator that acts as a secondary metabolic checkpoint to orchestrate the adaptive response of NK cells during viral infection.
Asunto(s)
Infecciones por Citomegalovirus , Virosis , Humanos , Ratones , Animales , Inmunidad Entrenada , Células Asesinas Naturales , Linfocitos T CD8-positivos , Memoria InmunológicaRESUMEN
Cytokine signaling via signal transducer and activator of transcription (STAT) proteins is crucial for optimal antiviral responses of natural killer (NK) cells. However, the pleiotropic effects of both cytokine and STAT signaling preclude the ability to precisely attribute molecular changes to specific cytokine-STAT modules. Here, we employed a multi-omics approach to deconstruct and rebuild the complex interaction of multiple cytokine signaling pathways in NK cells. Proinflammatory cytokines and homeostatic cytokines formed a cooperative axis to commonly regulate global gene expression and to further repress expression induced by type I interferon signaling. These cytokines mediated distinct modes of epigenetic regulation via STAT proteins, and collective signaling best recapitulated global antiviral responses. The most dynamically responsive genes were conserved across humans and mice, which included a cytokine-STAT-induced cross-regulatory program. Thus, an intricate crosstalk exists between cytokine signaling pathways, which governs NK cell responses.
Asunto(s)
Epigénesis Genética/inmunología , Infecciones por Herpesviridae/inmunología , Interleucinas/metabolismo , Células Asesinas Naturales/inmunología , Factores de Transcripción STAT/metabolismo , Animales , Separación Celular , Secuenciación de Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Redes Reguladoras de Genes/inmunología , Infecciones por Herpesviridae/sangre , Infecciones por Herpesviridae/virología , Humanos , Inmunidad Innata/genética , Células Asesinas Naturales/metabolismo , Masculino , Ratones , Ratones Noqueados , Muromegalovirus/inmunología , Análisis de Componente Principal , RNA-Seq , Factores de Transcripción STAT/genética , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.
Asunto(s)
Ayuno , Células Asesinas Naturales , Ratones Endogámicos C57BL , Animales , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Ratones , Humanos , Neoplasias/inmunología , Médula Ósea/inmunología , Médula Ósea/metabolismo , Ratones Noqueados , Interferón gamma/metabolismo , Interferón gamma/inmunología , Bazo/inmunología , Bazo/metabolismo , Inmunidad Innata/inmunología , Interleucina-12/metabolismo , Interleucina-12/inmunología , Receptores CXCR4/metabolismoRESUMEN
Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue residency being cardinal features. A corresponding role for innate cells is unknown. Here, we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived, tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ T cells. Thus, NK cells develop adaptive-like features, including long-term residency in non-lymphoid tissues, to modulate inflammation, restore immune equilibrium, and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases.
Asunto(s)
Infecciones por Citomegalovirus , Muromegalovirus , Humanos , Animales , Ratones , Células Asesinas Naturales , Inmunidad Adaptativa , Linfocitos T , Inmunidad InnataRESUMEN
Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Whether tissue-resident lymphocytes confer early antiviral immunity at local sites of primary infection prior to the initiation of circulating responses is not well understood. Furthermore, the kinetics of initial antiviral responses at sites of infection remain unclear. Here, we show that tissue-resident type 1 innate lymphoid cells (ILC1) serve an essential early role in host immunity through rapid production of interferon (IFN)-γ following viral infection. Ablation of Zfp683-dependent liver ILC1 lead to increased viral load in the presence of intact adaptive and innate immune cells critical for mouse cytomegalovirus (MCMV) clearance. Swift production of interleukin (IL)-12 by tissue-resident XCR1+ conventional dendritic cells (cDC1) promoted ILC1 production of IFN-γ in a STAT4-dependent manner to limit early viral burden. Thus, ILC1 contribute an essential role in viral immunosurveillance at sites of initial infection in response to local cDC1-derived proinflammatory cytokines.
Asunto(s)
Infecciones por Herpesviridae/inmunología , Linfocitos/inmunología , Muromegalovirus/fisiología , Animales , Infecciones por Herpesviridae/patología , Inmunidad Innata , Vigilancia Inmunológica , Inflamación/inmunología , Interferón gamma/inmunología , Células Asesinas Naturales/inmunología , Hígado/citología , Hígado/inmunología , Ratones Endogámicos C57BL , Cavidad Peritoneal/citología , Replicación ViralRESUMEN
Innate lymphoid cells (ILCs) are tissue-resident sentinels that are essential for early host protection from pathogens at initial sites of infection. However, whether pathogen-derived antigens directly modulate the responses of tissue-resident ILCs has remained unclear. In the present study, it was found that liver-resident type 1 ILCs (ILC1s) expanded locally and persisted after the resolution of infection with mouse cytomegalovirus (MCMV). ILC1s acquired stable transcriptional, epigenetic and phenotypic changes a month after the resolution of MCMV infection, and showed an enhanced protective effector response to secondary challenge with MCMV consistent with a memory lymphocyte response. Memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, and were independent of bystander activation by proinflammatory cytokines after heterologous infection. Thus, liver ILC1s acquire adaptive features in an MCMV-specific manner.
Asunto(s)
Memoria Inmunológica/inmunología , Hígado/inmunología , Linfocitos/inmunología , Glicoproteínas de Membrana/inmunología , Muromegalovirus/inmunología , Proteínas del Envoltorio Viral/inmunología , Animales , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Inmunidad Innata/inmunología , Subunidad alfa del Receptor de Interleucina-18/metabolismo , Hígado/citología , RatonesRESUMEN
Natural killer (NK) cells are critical mediators of host immunity to pathogens. Here, we demonstrate that the endoplasmic reticulum stress sensor inositol-requiring enzyme 1 (IRE1α) and its substrate transcription factor X-box-binding protein 1 (XBP1) drive NK cell responses against viral infection and tumors in vivo. IRE1α-XBP1 were essential for expansion of activated mouse and human NK cells and are situated downstream of the mammalian target of rapamycin signaling pathway. Transcriptome and chromatin immunoprecipitation analysis revealed c-Myc as a new and direct downstream target of XBP1 for regulation of NK cell proliferation. Genetic ablation or pharmaceutical blockade of IRE1α downregulated c-Myc, and NK cells with c-Myc haploinsufficency phenocopied IRE1α-XBP1 deficiency. c-Myc overexpression largely rescued the proliferation defect in IRE1α-/- NK cells. Like c-Myc, IRE1α-XBP1 also promotes oxidative phosphorylation in NK cells. Overall, our study identifies a IRE1α-XBP1-cMyc axis in NK cell immunity, providing insight into host protection against infection and cancer.
Asunto(s)
Estrés del Retículo Endoplásmico/genética , Endorribonucleasas/genética , Regulación de la Expresión Génica , Genes myc , Inmunidad/genética , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Animales , Biomarcadores , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Citotoxicidad Inmunológica , Interacciones Huésped-Patógeno/inmunología , Humanos , Activación de Linfocitos/inmunología , Melanoma Experimental , Ratones , Ratones Noqueados , Mitocondrias/metabolismo , Fosforilación Oxidativa , Transducción de Señal , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Clonal expansion and immunological memory are hallmark features of the mammalian adaptive immune response and essential for prolonged host control of pathogens. Recent work demonstrates that natural killer (NK) cells of the innate immune system also exhibit these adaptive traits during infection. Here we demonstrate that differentiating and 'memory' NK cells possess distinct chromatin accessibility states and that their epigenetic profiles reveal a 'poised' regulatory program at the memory stage. Furthermore, we elucidate how individual STAT transcription factors differentially control epigenetic and transcriptional states early during infection. Finally, concurrent chromatin profiling of the canonical CD8+ T cell response against the same infection demonstrated parallel and distinct epigenetic signatures defining NK cells and CD8+ T cells. Overall, our study reveals the dynamic nature of epigenetic modifications during the generation of innate and adaptive lymphocyte memory.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Cromatina/metabolismo , Infecciones por Herpesviridae/inmunología , Células Asesinas Naturales/fisiología , Muromegalovirus/fisiología , Factor de Transcripción STAT1/metabolismo , Factor de Transcripción STAT4/metabolismo , Inmunidad Adaptativa , Animales , Células Cultivadas , Cromatina/genética , Selección Clonal Mediada por Antígenos , Epigénesis Genética , Perfilación de la Expresión Génica , Inmunidad Innata , Memoria Inmunológica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT4/genéticaRESUMEN
Upon viral infection, natural killer (NK) cells expressing certain germline-encoded receptors are selected, expanded, and maintained in an adaptive-like manner. Currently, these are thought to differentiate along a common pathway. However, by fate mapping of single NK cells upon murine cytomegalovirus (MCMV) infection, we identified two distinct NK cell lineages that contributed to adaptive-like responses. One was equivalent to conventional NK (cNK) cells while the other was transcriptionally similar to type 1 innate lymphoid cells (ILC1s). ILC1-like NK cells showed splenic residency and strong cytokine production but also recognized and killed MCMV-infected cells, guided by activating receptor Ly49H. Moreover, they induced clustering of conventional type 1 dendritic cells and facilitated antigen-specific T cell priming early during MCMV infection, which depended on Ly49H and the NK cell-intrinsic expression of transcription factor Batf3. Thereby, ILC1-like NK cells bridge innate and adaptive viral recognition and unite critical features of cNK cells and ILC1s.
Asunto(s)
Inmunidad Adaptativa/inmunología , Linaje de la Célula/inmunología , Infecciones por Herpesviridae/inmunología , Inmunidad Innata/inmunología , Células Asesinas Naturales/inmunología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MuromegalovirusRESUMEN
Macrophage activation is controlled by a balance between activating and inhibitory receptors1-7, which protect normal tissues from excessive damage during infection8,9 but promote tumour growth and metastasis in cancer7,10. Here we report that the Kupffer cell lineage-determining factor ID3 controls this balance and selectively endows Kupffer cells with the ability to phagocytose live tumour cells and orchestrate the recruitment, proliferation and activation of natural killer and CD8 T lymphoid effector cells in the liver to restrict the growth of a variety of tumours. ID3 shifts the macrophage inhibitory/activating receptor balance to promote the phagocytic and lymphoid response, at least in part by buffering the binding of the transcription factors ELK1 and E2A at the SIRPA locus. Furthermore, loss- and gain-of-function experiments demonstrate that ID3 is sufficient to confer this potent anti-tumour activity to mouse bone-marrow-derived macrophages and human induced pluripotent stem-cell-derived macrophages. Expression of ID3 is therefore necessary and sufficient to endow macrophages with the ability to form an efficient anti-tumour niche, which could be harnessed for cell therapy in cancer.
Asunto(s)
Proteínas Inhibidoras de la Diferenciación , Macrófagos del Hígado , Neoplasias , Animales , Humanos , Ratones , Células de la Médula Ósea/citología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linaje de la Célula , Células Madre Pluripotentes Inducidas/citología , Proteínas Inhibidoras de la Diferenciación/deficiencia , Proteínas Inhibidoras de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Macrófagos del Hígado/citología , Macrófagos del Hígado/inmunología , Macrófagos del Hígado/metabolismo , Hígado/inmunología , Hígado/patología , Activación de Macrófagos , Proteínas de Neoplasias , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , FagocitosisRESUMEN
Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.
Asunto(s)
Cromatina/genética , Cromatina/metabolismo , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , G-Cuádruplex , Síndrome de Inmunodeficiencia con Hiper-IgM/etiología , Síndrome de Inmunodeficiencia con Hiper-IgM/metabolismo , Mutación , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biología Computacional/métodos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Activación Enzimática , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/diagnóstico , Cambio de Clase de Inmunoglobulina/genética , Cambio de Clase de Inmunoglobulina/inmunología , Inmunofenotipificación , Activación de Linfocitos/genética , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones TransgénicosRESUMEN
The emergence of recombination-activating genes (RAGs) in jawed vertebrates endowed adaptive immune cells with the ability to assemble a diverse set of antigen receptor genes. In contrast, innate lymphocytes, such as natural killer (NK) cells, are not believed to require RAGs. Here, we report that NK cells unable to express RAGs or RAG endonuclease activity during ontogeny exhibit a cell-intrinsic hyperresponsiveness but a diminished capacity to survive following virus-driven proliferation, a reduced expression of DNA damage response mediators, and defects in the repair of DNA breaks. Evidence for this novel function of RAG has also been observed in T cells and innate lymphoid cells (ILCs), revealing an unexpected role for RAG proteins beyond V(D)J recombination. We propose that DNA cleavage events mediated by RAG endow developing adaptive and innate lymphocytes with a cellular "fitness" that safeguards their persistence later in life during episodes of rapid proliferation or cellular stress.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas de Homeodominio/metabolismo , Células Asesinas Naturales/inmunología , Animales , Infecciones por Citomegalovirus/inmunología , Roturas del ADN de Doble Cadena , Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones SCID , Muromegalovirus/fisiología , Células Madre/citología , Células Madre/metabolismo , Recombinación V(D)JRESUMEN
Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFß. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.