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1.
Immunity ; 51(3): 479-490.e6, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31402259

RESUMO

Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.

2.
Front Immunol ; 10: 1423, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312200

RESUMO

The gastrointestinal tract hosts the largest collection of commensal microbes in the body. Infections at this site can cause significant perturbations in the microbiota, known as dysbiosis, that facilitate the expansion of pathobionts, and can elicit inappropriate immune responses that impair the intestinal barrier function. Dysbiosis typically occurs during intestinal infection with Toxoplasma gondii. Host resistance to T. gondii depends on a potent Th1 response. In addition, a Th17 response is also elicited. How Th17 cells contribute to the host response to T. gondii remains unclear. Here we show that class I-restricted T cell-associated molecule (CRTAM) expression on T cells is required for an optimal IL-17 production during T. gondii infection. Moreover, that the lack of IL-17, results in increased immunopathology caused by an impaired antimicrobial peptide production and bacterial translocation from the intestinal lumen to the mesenteric lymph nodes and spleen.

3.
Nat Immunol ; 18(9): 995-1003, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28759002

RESUMO

Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-ß family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-ß family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-ß signaling mediated by the cytokine receptor TGFßR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-ß. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-ß signaling in NK cells.


Assuntos
Células Matadoras Naturais/citologia , Linfopoese/genética , Proteína Smad4/genética , Fator de Crescimento Transformador beta/imunologia , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/imunologia , Animais , Estudos de Casos e Controles , Diferenciação Celular , Perfilação da Expressão Gênica , Humanos , Imunidade Inata/imunologia , Immunoblotting , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Linfócitos/citologia , Melanoma Experimental/imunologia , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Proteína Smad4/imunologia
4.
Science ; 357(6353): 806-810, 2017 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-28775213

RESUMO

The small intestine contains CD4+CD8αα+ double-positive intraepithelial lymphocytes (DP IELs), which originate from intestinal CD4+ T cells through down-regulation of the transcription factor Thpok and have regulatory functions. DP IELs are absent in germ-free mice, which suggests that their differentiation depends on microbial factors. We found that DP IEL numbers in mice varied in different vivaria, correlating with the presence of Lactobacillus reuteri This species induced DP IELs in germ-free mice and conventionally-raised mice lacking these cells. L. reuteri did not shape the DP-IEL-TCR (TCR, T cell receptor) repertoire but generated indole derivatives of tryptophan that activated the aryl-hydrocarbon receptor in CD4+ T cells, allowing Thpok down-regulation and differentiation into DP IELs. Thus, L. reuteri, together with a tryptophan-rich diet, can reprogram intraepithelial CD4+ T cells into immunoregulatory T cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Microbioma Gastrointestinal/imunologia , Intestino Delgado/imunologia , Intestino Delgado/microbiologia , Lactobacillus reuteri/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação para Baixo , Vida Livre de Germes , Indóis/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição/metabolismo , Triptofano/metabolismo
5.
Immunol Lett ; 179: 19-24, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27394699

RESUMO

Innate lymphoid cells (ILCs) are a heterogeneous population of cells with diverse roles in immune responses. Three major groups of ILCs have been defined on the basis of similarity in their production of signature cytokines, developmental requirements, and phenotypic markers. Group 1 ILCs produce IFN-γ, express the T-box transcription factors (TF) T-bet and/or Eomesodermin (Eomes), group 2 ILCs secrete IL-5 and IL-13 and express the TF GATA-3, while group 3 ILCs produce IL-22 and IL-17 and express the TF RORgt. In this review, we will briefly overview each group in terms of phenotype, function and development and then focus more extensively on group 1 ILCs, expanding on their emerging diversity, their disparate functions and the differences between NK cells and ILC1.


Assuntos
Plasticidade Celular/imunologia , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Plasticidade Celular/genética , Citocinas/metabolismo , Suscetibilidade a Doenças , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Interferon gama/biossíntese , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subpopulações de Linfócitos/citologia , Especificidade de Órgãos , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
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
7.
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 Genética/genética , Transcrição Genética/imunologia , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Curr Opin Immunol ; 32: 71-7, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25615701

RESUMO

Here, we illustrate the complexity of ILC subsets and discuss novel functions, focusing on emerging mechanisms of crosstalk with other immune cells and the microbiota. Furthermore, we highlight recent insights into the development of ILCs, including the common pathways they share as well as points of divergence between ILC groups and subsets.


Assuntos
Diferenciação Celular , Imunidade Inata , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/fisiologia , Animais , Humanos , Células Progenitoras Linfoides/citologia , Fenótipo
9.
J Immunol ; 192(10): 4487-91, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24740507

RESUMO

Nfil3 is viewed as an obligate transcription factor for NK cell development. However, mouse CMV (MCMV) infection recently was shown to bypass the requirement for Nfil3 by inducing the appearance of NK cells that express the MCMV-specific receptor Ly49H. Thus, signals transmitted by Ly49H and proinflammatory cytokines are sufficient to promote NK cell differentiation in the absence of Nfil3. In this study, we report that salivary gland (SG) NK cells develop in an Nfil3-independent fashion in the steady-state in the absence of MCMV or any infection. Moreover, we show that SG NK cells have an integrin profile reminiscent of tissue-resident lymphocytes and express TRAIL for killing target cells. These results demonstrate that SG NK cells, although related to conventional NK cells, are a distinct subset of innate lymphoid cells that deviates from the conventional developmental pathway, perhaps under the influence of tissue-specific factors.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Diferenciação Celular/imunologia , Células Matadoras Naturais/imunologia , Glândulas Salivares/imunologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Diferenciação Celular/genética , Infecções por Herpesviridae/genética , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/patologia , Células Matadoras Naturais/patologia , Camundongos , Camundongos Knockout , Muromegalovirus/imunologia , Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília A de Receptores Semelhantes a Lectina de Células NK/imunologia , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Glândulas Salivares/patologia , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/imunologia
10.
J Exp Med ; 211(4): 623-33, 2014 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-24687959

RESUMO

Retention of lymphocytes in the intestinal mucosa requires specialized chemokine receptors and adhesion molecules. We find that both CD4(+)CD8(+) and CD4(+) T cells in the intestinal epithelium, as well as CD8(+) T cells in the intestinal mucosa and mesenteric lymph nodes, express the cell adhesion molecule class I-restricted T cell-associated molecule (Crtam) upon activation, whereas the ligand of Crtam, cell adhesion molecule 1 (Cadm1), is expressed on gut CD103(+)DCs. Lack of Crtam-Cadm1 interactions in Crtam(-/-) and Cadm1(-/-) mice results in loss of CD4(+)CD8(+) T cells, which arise from mucosal CD4(+) T cells that acquire a CD8 lineage expression profile. After acute oral infection with Toxoplasma gondii, both WT and Crtam(-/-) mice mounted a robust TH1 response, but markedly fewer TH17 cells were present in the intestinal mucosa of Crtam(-/-) mice. The almost exclusive TH1 response in Crtam(-/-) mice resulted in more efficient control of intestinal T. gondii infection. Thus, Crtam-Cadm1 interactions have a major impact on the residency and maintenance of CD4(+)CD8(+) T cells in the gut mucosa in the steady state. During pathogenic infection, Crtam-Cadm1 interactions regulate the dynamic equilibrium between newly formed CD4(+) T cells and their retention in the gut, thereby shaping representation of disparate CD4(+) T cell subsets and the overall quality of the CD4(+) T cell response.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/parasitologia , Imunoglobulinas/metabolismo , Células Th17/imunologia , Toxoplasma/fisiologia , Animais , Molécula 1 de Adesão Celular , Moléculas de Adesão Celular/metabolismo , Polaridade Celular , Citocinas/biossíntese , Células Dendríticas/metabolismo , Trato Gastrointestinal/patologia , Imunoglobulinas/deficiência , Interleucina-17/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/parasitologia , Mucosa Intestinal/patologia , Ligantes , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização , Toxoplasmose Animal/imunologia , Toxoplasmose Animal/parasitologia
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