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1.
Nat Immunol ; 16(11): 1124-33, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26414766

RESUMO

Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses to external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 subsets, the transcriptional control of commitment to each ILC lineage is incompletely understood. Here we report that the transcription factor Runx3 was essential for the normal development of ILC1 and ILC3 cells but not of ILC2 cells. Runx3 controlled the survival of ILC1 cells but not of ILC3 cells. Runx3 was required for expression of the transcription factor RORγt and its downstream target, the transcription factor AHR, in ILC3 cells. The absence of Runx3 in ILCs exacerbated infection with Citrobacter rodentium. Therefore, our data establish Runx3 as a key transcription factor in the lineage-specific differentiation of ILC1 and ILC3 cells.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Animais , Antígenos Ly/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Subunidade alfa 3 de Fator de Ligação ao Core/deficiência , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/deficiência , Subunidade beta de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/metabolismo , Infecções por Enterobacteriaceae/etiologia , Infecções por Enterobacteriaceae/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Subpopulações de Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/deficiência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo
2.
J Immunol ; 203(7): 1981-1988, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31444264

RESUMO

NK cells can recognize target cells such as virus-infected and tumor cells through integration of activation and inhibitory receptors. Recognition by NK cells can lead to direct lysis of the target cell and production of the signature cytokine IFN-γ. However, it is unclear whether stimulation through activation receptors alone is sufficient for IFN-γ production. In this study, we show that NK activation receptor engagement requires additional signals for optimal IFN-γ production, which could be provided by IFN-ß or IL-12. Stimulation of murine NK cells with soluble Abs directed against NK1.1, Ly49H, Ly49D, or NKp46 required additional stimulation with cytokines, indicating that a range of activation receptors with distinct adaptor molecules require additional stimulation for IFN-γ production. The requirement for multiple signals extends to stimulation with primary m157-transgenic target cells, which triggers the activation receptor Ly49H, suggesting that NK cells do require multiple signals for IFN-γ production in the context of target cell recognition. Using quantitative PCR and RNA flow cytometry, we found that cytokines, not activating ligands, act on NK cells to express Ifng transcripts. Ly49H engagement is required for IFN-γ translational initiation. Results using inhibitors suggest that the proteasome-ubiquitin-IKK-TPL2-MNK1 axis was required during activation receptor engagement. Thus, this study indicates that activation receptor-dependent IFN-γ production is regulated on the transcriptional and translational levels.


Assuntos
Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Complexo de Endopeptidases do Proteassoma/imunologia , Biossíntese de Proteínas/imunologia , Transdução de Sinais/imunologia , Transcrição Gênica/imunologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Interferon gama/genética , Células Matadoras Naturais/citologia , Camundongos , Camundongos Knockout , Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/imunologia , Complexo de Endopeptidases do Proteassoma/genética , Transdução de Sinais/genética
3.
J Immunol ; 201(9): 2551-2556, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275046

RESUMO

NK cells accumulate in adult murine and human uteri during decidualization induced physiologically, pathologically, or experimentally. Adoptive transfer studies indicate that uterine NK (uNK) cells arise from circulating progenitors. However, virgin uteri contain few circulating NK1.1+CD49a- conventional NK cells, whereas NK1.1+CD49a+ tissue-resident NK (trNK) cells are abundant. In this study, we employed a novel, immune-competent NK cell-specific reporter mouse to track accumulation of uNK cells during unmanipulated pregnancies. We identified conventional NK and trNK cells accumulating in both decidua basalis and myometrium. Only trNK cells showed evidence of proliferation. In parabiosis studies using experimentally induced deciduomata, the accumulated uNK cells were proliferating trNK cells; migrating NK cells made no contribution. Together, these data suggest proliferating trNK cells are the source of uNK cells during endometrial decidualization.


Assuntos
Movimento Celular/imunologia , Proliferação de Células/fisiologia , Decídua/citologia , Células Matadoras Naturais/imunologia , Prenhez , Animais , Antígenos Ly/genética , Antígenos Ly/metabolismo , Decídua/imunologia , Feminino , Proteínas de Fluorescência Verde/genética , Células Matadoras Naturais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Receptor 1 Desencadeador da Citotoxicidade Natural/genética , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Parabiose , Gravidez
4.
J Virol ; 91(9)2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28179532

RESUMO

The human roseoloviruses human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 comprise the Roseolovirus genus of the human Betaherpesvirinae subfamily. Infections with these viruses have been implicated in many diseases; however, it has been challenging to establish infections with roseoloviruses as direct drivers of pathology, because they are nearly ubiquitous and display species-specific tropism. Furthermore, controlled study of infection has been hampered by the lack of experimental models, and until now, a mouse roseolovirus has not been identified. Herein we describe a virus that causes severe thymic necrosis in neonatal mice, characterized by a loss of CD4+ T cells. These phenotypes resemble those caused by the previously described mouse thymic virus (MTV), a putative herpesvirus that has not been molecularly characterized. By next-generation sequencing of infected tissue homogenates, we assembled a contiguous 174-kb genome sequence containing 128 unique predicted open reading frames (ORFs), many of which were most closely related to herpesvirus genes. Moreover, the structure of the virus genome and phylogenetic analysis of multiple genes strongly suggested that this virus is a betaherpesvirus more closely related to the roseoloviruses, HHV-6A, HHV-6B, and HHV-7, than to another murine betaherpesvirus, mouse cytomegalovirus (MCMV). As such, we have named this virus murine roseolovirus (MRV) because these data strongly suggest that MRV is a mouse homolog of HHV-6A, HHV-6B, and HHV-7.IMPORTANCE Herein we describe the complete genome sequence of a novel murine herpesvirus. By sequence and phylogenetic analyses, we show that it is a betaherpesvirus most closely related to the roseoloviruses, human herpesviruses 6A, 6B, and 7. These data combined with physiological similarities with human roseoloviruses collectively suggest that this virus is a murine roseolovirus (MRV), the first definitively described rodent roseolovirus, to our knowledge. Many biological and clinical ramifications of roseolovirus infection in humans have been hypothesized, but studies showing definitive causative relationships between infection and disease susceptibility are lacking. Here we show that MRV infects the thymus and causes T-cell depletion, suggesting that other roseoloviruses may have similar properties.


Assuntos
Modelos Animais de Doenças , Herpesviridae/classificação , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Depleção Linfocítica , Infecções por Roseolovirus/virologia , Animais , Sequência de Bases , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , DNA Viral/genética , Genoma Viral/genética , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Fases de Leitura Aberta/genética , Filogenia , Análise de Sequência de DNA , Timo/virologia
5.
J Exp Med ; 220(11)2023 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-37698554

RESUMO

Natural killer (NK) cells are lymphocytes capable of controlling tumors and virus infections through direct lysis and cytokine production. While both T and NK cells expand and accumulate in affected tissues, the role of NK cell expansion in tumor and viral control is not well understood. Here, we show that posttranscriptional regulation by the RNA-binding protein HuR is essential for NK cell expansion without negatively affecting effector functions. HuR-deficient NK cells displayed defects in the metaphase of the cell cycle, including decreased expression and alternative splicing of Ska2, a component of the spindle and kinetochore complex. HuR-dependent NK cell expansion contributed to long-term cytomegalovirus control and facilitated control of subcutaneous tumors but not tumor metastases in two independent tumor models. These results show that posttranscriptional regulation by HuR specifically affects NK cell expansion, which is required for the control of long-term virus infection and solid tumors, but not acute infection or tumor metastases, highlighting fundamental differences with antigen-specific T cell control.


Assuntos
Proteína Semelhante a ELAV 1 , Células Matadoras Naturais , Neoplasias , Viroses , Humanos , Ciclo Celular , Divisão Celular , Proliferação de Células , Proteína Semelhante a ELAV 1/metabolismo , Proteínas Cromossômicas não Histona/metabolismo
6.
Cell Rep ; 32(4): 107969, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32726632

RESUMO

Major histocompatibility complex class I (MHC-I)-restricted immune responses are largely attributed to cytotoxic T lymphocytes (CTLs). However, natural killer (NK) cells, as predicted by the missing-self hypothesis, have opposing requirements for MHC-I, suggesting that they may also demonstrate MHC-I-restricted effects. In mice, the Ly49 inhibitory receptors prevent NK cell killing of missing-self targets in effector responses, and they have a proposed second function in licensing or educating NK cells via self-MHC-I in vivo. Here we show MHC-I-restricted control of murine cytomegalovirus (MCMV) infection in vivo that is NK cell dependent. Using mice lacking specific Ly49 receptors, we show that control of MCMV requires inhibitory Ly49 receptors and an inhibitory signaling motif and the capacity for MCMV to downregulate MHC-I. Taken together, these data provide definitive evidence that the inhibitory receptors are required for missing-self rejection and are relevant to MHC-I-restricted NK cell control of a viral infection in vivo.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/metabolismo , Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo , Animais , Antígenos Ly , Infecções por Citomegalovirus/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Muromegalovirus/patogenicidade , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores de Células Matadoras Naturais , Viroses
7.
Elife ; 82019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393266

RESUMO

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe Toxoplasma gondii infection converts NK cells into ILC1-like cells that are distinct from both steady-state NK cells and ILC1s in uninfected mice. These cells were Eomes-dependent, indicating that NK cells can give rise to Eomes- Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.


Assuntos
Transdiferenciação Celular , Células Matadoras Naturais/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Modelos Animais de Doenças , Camundongos , Proteínas com Domínio T/metabolismo
8.
Oncoimmunology ; 5(12): e1238543, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28123874

RESUMO

Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the X-chromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.

9.
Elife ; 3: e01659, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24714492

RESUMO

Natural killer (NK) cells belong to the innate immune system; they can control virus infections and developing tumors by cytotoxicity and producing inflammatory cytokines. Most studies of mouse NK cells, however, have focused on conventional NK (cNK) cells in the spleen. Recently, we described two populations of liver NK cells, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, their lineage relationship was unclear; trNK cells could be developing cNK cells, related to thymic NK cells, or a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis and transcription factor-deficient mice to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells. Taken together with analysis of trNK cells in other tissues, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells. DOI: http://dx.doi.org/10.7554/eLife.01659.001.


Assuntos
Linhagem da Célula , Células Matadoras Naturais/imunologia , Fígado/imunologia , Pele/imunologia , Baço/imunologia , Timo/imunologia , Útero/imunologia , Animais , Biomarcadores/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunofenotipagem , Células Matadoras Naturais/metabolismo , Fígado/citologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Pele/citologia , Pele/metabolismo , Baço/citologia , Baço/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Útero/citologia , Útero/metabolismo
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