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1.
Annu Rev Immunol ; 37: 521-546, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30726153

RESUMO

Resident memory T (Trm) cells stably occupy tissues and cannot be sampled in superficial venous blood. Trm cells are heterogeneous but collectively constitute the most abundant memory T cell subset. Trm cells form an integral part of the immune sensing network, monitor for local perturbations in homeostasis throughout the body, participate in protection from infection and cancer, and likely promote autoimmunity, allergy, and inflammatory diseases and impede successful transplantation. Thus Trm cells are major candidates for therapeutic manipulation. Here we review CD8+ and CD4+ Trm ontogeny, maintenance, function, and distribution within lymphoid and nonlymphoid tissues and strategies for their study. We briefly discuss other resident leukocyte populations, including innate lymphoid cells, macrophages, natural killer and natural killer T cells, nonclassical T cells, and memory B cells. Lastly, we highlight major gaps in knowledge and propose ways in which a deeper understanding could result in new methods to prevent or treat diverse human diseases.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/fisiologia , Leucócitos/imunologia , Macrófagos/imunologia , Animais , Movimento Celular , Humanos , Imunidade Inata , Memória Imunológica , Especificidade de Órgãos
2.
Cell ; 180(6): 1280-1280.e1, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32200803

RESUMO

NK cells are broadly distributed innate lymphoid cells (ILCs) encompassing distinct populations based on CD11b and CD27 expression in mice or CD56 intensity in humans. Involved in anti-viral and anti-tumor immunity thanks to their cytokines and chemokines secretion as well as their cytotoxic capabilities, NK cells have emerged as a promising therapeutic target in several solid tumors and hematological malignancies. To view this Snapshot, open or download the PDF.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/fisiologia , Animais , Citocinas/metabolismo , Humanos , Imunidade Inata , Imunoterapia Ativa/métodos , Camundongos , Neoplasias/imunologia
3.
Cell ; 180(4): 749-763.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32059780

RESUMO

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.


Assuntos
Envelhecimento/imunologia , Células Matadoras Naturais/citologia , Linfopoese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Inata , Mucosa Intestinal/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Pulmão/citologia , Linfonodos/citologia , Masculino , Pessoa de Meia-Idade , Baço/citologia
4.
Cell ; 176(1-2): 348-360.e12, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30595449

RESUMO

Natural killer (NK) cells develop from common progenitors but diverge into distinct subsets, which differ in cytokine production, cytotoxicity, homing, and memory traits. Given their promise in adoptive cell therapies for cancer, a deeper understanding of regulatory modules controlling clinically beneficial NK phenotypes is of high priority. We report integrated "-omics" analysis of human NK subsets, which revealed super-enhancers associated with gene cohorts that may coordinate NK functions and localization. A transcription factor-based regulatory scheme also emerged, which is evolutionarily conserved and shared by innate and adaptive lymphocytes. For both NK and T lineages, a TCF1-LEF1-MYC axis dominated the regulatory landscape of long-lived, proliferative subsets that traffic to lymph nodes. In contrast, effector populations circulating between blood and peripheral tissues shared a PRDM1-dominant landscape. This resource defines transcriptional modules, regulated by feedback loops, which may be leveraged to enhance phenotypes for NK cell-based therapies.


Assuntos
Células Matadoras Naturais/classificação , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Citocinas/imunologia , Citocinas/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Fenótipo
5.
Cell ; 176(4): 716-728.e18, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30712871

RESUMO

Sensory axons degenerate following separation from their cell body, but partial injury to peripheral nerves may leave the integrity of damaged axons preserved. We show that an endogenous ligand for the natural killer (NK) cell receptor NKG2D, Retinoic Acid Early 1 (RAE1), is re-expressed in adult dorsal root ganglion neurons following peripheral nerve injury, triggering selective degeneration of injured axons. Infiltration of cytotoxic NK cells into the sciatic nerve by extravasation occurs within 3 days following crush injury. Using a combination of genetic cell ablation and cytokine-antibody complex stimulation, we show that NK cell function correlates with loss of sensation due to degeneration of injured afferents and reduced incidence of post-injury hypersensitivity. This neuro-immune mechanism of selective NK cell-mediated degeneration of damaged but intact sensory axons complements Wallerian degeneration and suggests the therapeutic potential of modulating NK cell function to resolve painful neuropathy through the clearance of partially damaged nerves.


Assuntos
Células Matadoras Naturais/fisiologia , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Traumatismos dos Nervos Periféricos/metabolismo , Animais , Axônios , Gânglios Espinais/citologia , Gânglios Espinais/metabolismo , Células Matadoras Naturais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Regeneração Nervosa , Neurônios/citologia , Neurônios Aferentes/imunologia , Neurônios Aferentes/metabolismo , Proteínas Associadas à Matriz Nuclear/fisiologia , Proteínas de Transporte Nucleocitoplasmático/fisiologia , Dor , Traumatismos dos Nervos Periféricos/imunologia , Doenças do Sistema Nervoso Periférico , Nervo Isquiático , Células Receptoras Sensoriais/metabolismo
6.
Cell ; 175(2): 387-399.e17, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30270043

RESUMO

HIV-1 broadly neutralizing antibodies (bnAbs) are difficult to induce with vaccines but are generated in ∼50% of HIV-1-infected individuals. Understanding the molecular mechanisms of host control of bnAb induction is critical to vaccine design. Here, we performed a transcriptome analysis of blood mononuclear cells from 47 HIV-1-infected individuals who made bnAbs and 46 HIV-1-infected individuals who did not and identified in bnAb individuals upregulation of RAB11FIP5, encoding a Rab effector protein associated with recycling endosomes. Natural killer (NK) cells had the highest differential expression of RAB11FIP5, which was associated with greater dysregulation of NK cell subsets in bnAb subjects. NK cells from bnAb individuals had a more adaptive/dysfunctional phenotype and exhibited impaired degranulation and cytokine production that correlated with RAB11FIP5 transcript levels. Moreover, RAB11FIP5 overexpression modulated the function of NK cells. These data suggest that NK cells and Rab11 recycling endosomal transport are involved in regulation of HIV-1 bnAb development.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Anticorpos Neutralizantes/imunologia , Infecções por HIV/imunologia , Vacinas contra a AIDS/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Adulto , Linfócitos B/imunologia , Linhagem Celular , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica/métodos , Anticorpos Anti-HIV/imunologia , Infecções por HIV/fisiopatologia , HIV-1/patogenicidade , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Masculino , Pessoa de Meia-Idade
7.
Cell ; 175(2): 442-457.e23, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30290143

RESUMO

Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) critically contribute to the efficacy of anti-tumor therapeutic antibodies. We report here an unexpected finding that macrophages after ADCP inhibit NK cell-mediated ADCC and T cell-mediated cytotoxicity in breast cancers and lymphomas. Mechanistically, AIM2 is recruited to the phagosomes by FcγR signaling following ADCP and activated by sensing the phagocytosed tumor DNAs through the disrupted phagosomal membrane, which subsequently upregulates PD-L1 and IDO and causes immunosuppression. Combined treatment with anti-HER2 antibody and inhibitors of PD-L1 and IDO enhances anti-tumor immunity and anti-HER2 therapeutic efficacy in mouse models. Furthermore, neoadjuvant trastuzumab therapy significantly upregulates PD-L1 and IDO in the tumor-associated macrophages (TAMs) of HER2+ breast cancer patients, correlating with poor trastuzumab response. Collectively, our findings unveil a deleterious role of ADCP macrophages in cancer immunosuppression and suggest that therapeutic antibody plus immune checkpoint blockade may provide synergistic effects in cancer treatment.


Assuntos
Citotoxicidade Celular Dependente de Anticorpos/imunologia , Citofagocitose/imunologia , Macrófagos/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/fisiologia , Antígeno B7-H1/genética , Antígeno B7-H1/fisiologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Citofagocitose/fisiologia , Proteínas de Ligação a DNA/fisiologia , Modelos Animais de Doenças , Feminino , Humanos , Imunoterapia , Células Matadoras Naturais/fisiologia , Linfoma/imunologia , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fagocitose/imunologia , Fagocitose/fisiologia , Fagossomos/fisiologia , Receptores de IgG/imunologia
8.
Nat Immunol ; 19(9): 963-972, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30082830

RESUMO

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.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Cromatina/metabolismo , Infecções por Herpesviridae/imunologia , Células Matadoras Naturais/fisiologia , Muromegalovirus/fisiologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/metabolismo , Imunidade Adaptativa , Animais , Células Cultivadas , Cromatina/genética , Seleção Clonal Mediada por Antígeno , Epigênese Genética , Perfilação da Expressão Gênica , Imunidade Inata , Memória Imunológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT4/genética
9.
Nat Immunol ; 19(9): 954-962, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30127438

RESUMO

Controlling the balance between immunity and immunopathology is crucial for host resistance to pathogens. After infection, activation of the hypothalamic-pituitary-adrenal (HPA) axis leads to the production of glucocorticoids. However, the pleiotropic effects of these steroid hormones make it difficult to delineate their precise role(s) in vivo. Here we found that the regulation of natural killer (NK) cell function by the glucocorticoid receptor (GR) was required for host survival after infection with mouse cytomegalovirus (MCMV). Mechanistically, endogenous glucocorticoids produced shortly after infection induced selective and tissue-specific expression of the checkpoint receptor PD-1 on NK cells. This glucocorticoid-PD-1 pathway limited production of the cytokine IFN-γ by spleen NK cells, which prevented immunopathology. Notably, this regulation did not compromise viral clearance. Thus, the fine tuning of NK cell functions by the HPA axis preserved tissue integrity without impairing pathogen elimination, which reveals a novel aspect of neuroimmune regulation.


Assuntos
Glucocorticoides/metabolismo , Infecções por Herpesviridae/imunologia , Células Matadoras Naturais/fisiologia , Muromegalovirus/fisiologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Células Cultivadas , Feminino , Sistema Hipotálamo-Hipofisário , Imunidade Inata , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroimunomodulação , Especificidade de Órgãos , Sistema Hipófise-Suprarrenal , Receptores de Glucocorticoides/genética , Transdução de Sinais , Carga Viral
10.
Nat Immunol ; 16(3): 306-17, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25621825

RESUMO

The recognized diversity of innate lymphoid cells (ILCs) is rapidly expanding. Three ILC classes have emerged, ILC1, ILC2 and ILC3, with ILC1 and ILC3 including several subsets. The classification of some subsets is unclear, and it remains controversial whether natural killer (NK) cells and ILC1 cells are distinct cell types. To address these issues, we analyzed gene expression in ILCs and NK cells from mouse small intestine, spleen and liver, as part of the Immunological Genome Project. The results showed unique gene-expression patterns for some ILCs and overlapping patterns for ILC1 cells and NK cells, whereas other ILC subsets remained indistinguishable. We identified a transcriptional program shared by small intestine ILCs and a core ILC signature. We revealed and discuss transcripts that suggest previously unknown functions and developmental paths for ILCs.


Assuntos
Imunidade Inata/genética , Imunidade Inata/imunologia , Linfócitos/fisiologia , Transcrição Gênica/genética , Transcrição Gênica/imunologia , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Nat Immunol ; 16(6): 599-608, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25915732

RESUMO

Diverse innate lymphoid cell (ILC) subtypes have been defined on the basis of effector function and transcription factor expression. ILCs derive from common lymphoid progenitors, although the transcriptional pathways that lead to ILC-lineage specification remain poorly characterized. Here we found that the transcriptional regulator TOX was required for the in vivo differentiation of common lymphoid progenitors into ILC lineage-restricted cells. In vitro modeling demonstrated that TOX deficiency resulted in early defects in the survival or proliferation of progenitor cells, as well as ILC differentiation at a later stage. In addition, comparative transcriptome analysis of bone marrow progenitors revealed that TOX-deficient cells failed to upregulate many genes of the ILC program, including genes that are targets of Notch, which indicated that TOX is a key determinant of early specification to the ILC lineage.


Assuntos
Proteínas de Homeodomínio/metabolismo , Células Matadoras Naturais/fisiologia , Subpopulações de Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Receptores Notch/metabolismo , Animais , Células da Medula Óssea/fisiologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Feminino , Proteínas de Homeodomínio/genética , Imunidade Inata/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores Notch/genética , Transcriptoma
12.
Eur J Immunol ; 54(3): e2350693, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38279603

RESUMO

Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three-dimensional (3D) environments are critical for their functions under physiological conditions. However, the role of mechanosensing in regulating NK-cell killing efficiency in physiologically relevant scenarios is poorly understood. Here, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK-cell killing efficiency in 3D is impaired against softened tumor cells, whereas it is enhanced against stiffened tumor cells. Notably, the durations required for NK-cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel among the examined candidates in NK cells. Perturbation of PIEZO1 abolishes stiffness-dependent NK-cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK-cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1-mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK-cell killing efficiency under 3D physiological conditions and the influence of environmental physical cues on NK-cell functions.


Assuntos
Células Matadoras Naturais , Células Matadoras Naturais/fisiologia , Morte Celular
13.
Immunity ; 44(5): 1140-50, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27178467

RESUMO

The current model of murine innate lymphoid cell (ILC) development holds that mouse ILCs are derived downstream of the common lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor cells as well as human peripheral blood NK cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.


Assuntos
Células Matadoras Naturais/fisiologia , Linfonodos/imunologia , Subpopulações de Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Tonsila Palatina/imunologia , Adulto , Animais , Antígenos CD34/metabolismo , Diferenciação Celular , Linhagem Celular , Criança , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética
14.
Immunity ; 45(1): 74-82, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27438766

RESUMO

Natural killer (NK) cells are important in host defense against pathogens, and they can subsequently differentiate into memory NK cells. The Ly49 and KIR gene families in rodents and humans encode both inhibitory and activating receptors for MHC class I. The physiological role of activating KIR or Ly49 receptors that recognize self-MHC class I during immune response to viral infections is unknown. Here, we address how the activating Ly49D receptor impacts the NK cell response to mouse cytomegalovirus (MCMV) infection by comparing the activation and differentiation of Ly49D-bearing NK cells in mice lacking or expressing H-2D(d), the cognate MHC class I ligand of Ly49D. After MCMV infection, Ly49D augmented IFN-γ production by MCMV-specific Ly49H(+) NK cells and preferentially promoted the generation of memory Ly49H(+) NK cells. Thus, activating receptors for self-MHC class I modulate the differentiation of MCMV-specific NK cells and are beneficial for host defense against MCMV infection.


Assuntos
Infecções por Herpesviridae/imunologia , Memória Imunológica , Células Matadoras Naturais/fisiologia , Muromegalovirus/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo , Animais , Autoantígenos/genética , Autoantígenos/metabolismo , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Antígeno de Histocompatibilidade H-2D/genética , Antígeno de Histocompatibilidade H-2D/metabolismo , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/virologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos
15.
Immunity ; 44(5): 1127-39, 2016 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-27156386

RESUMO

The signals guiding differentiation of innate lymphoid cells (ILCs) within tissues are not well understood. Salivary gland (SG) ILCs as well as liver and intestinal intraepithelial ILC1 have markers that denote tissue residency and transforming growth factor-ß (TGF-ß) imprinting. We deleted Tgfbr2 in cells expressing the ILC and NK marker NKp46 and found that SG ILCs were reduced in number. They lost distinct tissue markers, such as CD49a, and the effector molecules TRAIL and CD73. Expression of the transcription factor Eomes, which promotes NK cell differentiation, was elevated. Conversely, Eomes deletion in NKp46(+) cells enhanced TGF-ß-imprinting of SG ILCs. Thus, TGF-ß induces SG ILC differentiation by suppressing Eomes. TGF-ß acted through a JNK-dependent, Smad4-independent pathway. Transcriptome analysis demonstrated that SG ILCs had characteristic of both NK cells and ILC1. Finally, TGF-ß imprinting of SG ILCs was synchronized with SG development, highlighting the impact of tissue microenvironment on ILC development.


Assuntos
Diferenciação Celular , Células Matadoras Naturais/fisiologia , Linfócitos/fisiologia , Glândulas Salivares/imunologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Antígenos Ly/metabolismo , Microambiente Celular , Perfilação da Expressão Gênica , Imunidade Inata , MAP Quinase Quinase 4/metabolismo , Camundongos , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteína Smad4/genética , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
16.
N Engl J Med ; 385(10): 921-929, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34469647

RESUMO

Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (IL2RG), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).


Assuntos
Mutação em Linhagem Germinativa , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/fisiologia , Infecções por Papillomavirus/terapia , Citotoxicidade Imunológica , Encefalite/virologia , Feminino , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Masculino , Microbiota/efeitos dos fármacos , Células T Matadoras Naturais/fisiologia , Papillomaviridae , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/imunologia , Linhagem , Pele/microbiologia , Transplante Homólogo , Adulto Jovem
17.
Immunity ; 43(2): 394-407, 2015 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-26287684

RESUMO

Natural killer (NK) cells are cytotoxic lymphocytes and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have been extensively characterized, the cellular stages of early human NK cell commitment remain poorly understood. Here we demonstrate that a Lin(-)CD34(+)CD38(+)CD123(-)CD45RA(+)CD7(+)CD10(+)CD127(-) population represents a NK lineage-restricted progenitor (NKP) in fetal development, umbilical cord blood, and adult tissues. The newly identified NKP has robust NK cell potential both in vitro and in vivo, generates functionally cytotoxic NK cells, and lacks the ability to produce T cells, B cells, myeloid cells, and innate lymphoid-like cells (ILCs). Our findings identify an early step to human NK cell commitment and provide new insights into the human hematopoietic hierarchy.


Assuntos
Sangue Fetal/citologia , Feto/citologia , Hematopoese , Células Matadoras Naturais/fisiologia , Células Progenitoras Linfoides/fisiologia , Adulto , Antígenos CD/metabolismo , Diferenciação Celular , Linhagem da Célula , Citotoxicidade Imunológica , Desenvolvimento Fetal , Hematopoese/imunologia , Humanos , Imunidade Inata , Imunofenotipagem
18.
PLoS Biol ; 19(8): e3001328, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34343168

RESUMO

Natural killer (NK) cells kill a target cell by secreting perforin into the lytic immunological synapse, a specialized interface formed between the NK cell and its target. Perforin creates pores in target cell membranes allowing delivery of proapoptotic enzymes. Despite the fact that secreted perforin is in close range to both the NK and target cell membranes, the NK cell typically survives while the target cell does not. How NK cells preferentially avoid death during the secretion of perforin via the degranulation of their perforin-containing organelles (lytic granules) is perplexing. Here, we demonstrate that NK cells are protected from perforin-mediated autolysis by densely packed and highly ordered presynaptic lipid membranes, which increase packing upon synapse formation. When treated with 7-ketocholesterol, lipid packing is reduced in NK cells making them susceptible to perforin-mediated lysis after degranulation. Using high-resolution imaging and lipidomics, we identified lytic granules themselves as having endogenously densely packed lipid membranes. During degranulation, lytic granule-cell membrane fusion thereby further augments presynaptic membrane packing, enhancing membrane protection at the specific sites where NK cells would face maximum concentrations of secreted perforin. Additionally, we found that an aggressive breast cancer cell line is perforin resistant and evades NK cell-mediated killing owing to a densely packed postsynaptic membrane. By disrupting membrane packing, these cells were switched to an NK-susceptible state, which could suggest strategies for improving cytotoxic cell-based cancer therapies. Thus, lipid membranes serve an unexpected role in NK cell functionality protecting them from autolysis, while degranulation allows for the inherent lytic granule membrane properties to create local ordered lipid "shields" against self-destruction.


Assuntos
Degranulação Celular , Células Matadoras Naturais/fisiologia , Lipídeos de Membrana/metabolismo , Perforina/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Voluntários Saudáveis , Humanos , Cetocolesteróis , Cultura Primária de Células
19.
Proc Natl Acad Sci U S A ; 118(31)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34330834

RESUMO

Therapies that boost the antitumor immune response have shown a great deal of success. Although most of these therapies have focused on enhancing T cell functions, there is a growing interest in developing therapies that can target other immune cell subsets. Like T cells, natural killer (NK) cells are cytotoxic effector cells that play a key role in the antitumor response. To advance the development of NK-based therapies, we developed a functional screen to rapidly identify antibodies that can activate NK cells. We displayed antibodies on a mammalian target cell line and probed their ability to stimulate NK cell-mediated cytotoxicity. From this screen, we identified five antibodies that bound with high affinity to NK cells and stimulated NK cell-mediated cytotoxicity and interferon-γ (IFN-γ) secretion. We demonstrate that these antibodies can be further developed into bispecific antibodies to redirect NK cell-mediated cytotoxicity toward CD20+ B cell lymphoma cells and HER2+ breast cancer cells. While antibodies to two of the receptors, CD16 and NCR1, have previously been targeted as bispecific antibodies to redirect NK cell-mediated cytotoxicity, we demonstrate that bispecific antibodies targeting NCR3 can also potently activate NK cells. These results show that this screen can be used to directly identify antibodies that can enhance antitumor immune responses.


Assuntos
Anticorpos/fisiologia , Citotoxicidade Celular Dependente de Anticorpos/fisiologia , Células Matadoras Naturais/fisiologia , Afinidade de Anticorpos , Neoplasias da Mama , Linhagem Celular Tumoral , Feminino , Proteínas Ligadas por GPI , Regulação da Expressão Gênica/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon gama/metabolismo , Linfoma de Células B/tratamento farmacológico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Superfície Celular , Receptores de IgG , Reprodutibilidade dos Testes , Rituximab/farmacologia
20.
PLoS Pathog ; 17(4): e1009531, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33878120

RESUMO

Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including natural killer (NK) cells. Lastly, the ability of Ncr1+ cell derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.


Assuntos
Listeria monocytogenes/imunologia , Listeriose/imunologia , Pneumonia/imunologia , Animais , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Interleucina-10/metabolismo , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/fisiologia , Lipopolissacarídeos , Listeria monocytogenes/patogenicidade , Listeriose/complicações , Listeriose/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doenças da Boca/complicações , Doenças da Boca/imunologia , Doenças da Boca/microbiologia , Doenças da Boca/patologia , Pneumonia/complicações , Pneumonia/etiologia , Pneumonia/patologia
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