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1.
Nat Immunol ; 24(1): 123-135, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36550322

RESUMO

Naive CD4+ T lymphocytes initially undergo antigen-specific activation to promote a broad-spectrum response before adopting bespoke cytokine expression profiles shaped by intercellular microenvironmental cues, resulting in pathogen-focused modular cytokine responses. Interleukin (IL)-4-induced Gata3 upregulation is important for the helper type 2 T cell (TH2 cell) polarization associated with anti-helminth immunity and misdirected allergic inflammation. Whether additional microenvironmental factors participate is unclear. Using whole mouse-genome CRISPR-Cas9 screens, we discovered a previously unappreciated role for αvß3 integrin in TH2 cell differentiation. Low-level αvß3 expression by naive CD4+ T cells contributed to pan-T cell activation by promoting T-T cell clustering and IL-2/CD25/STAT5 signaling. Subsequently, IL-4/Gata3-induced selective upregulation of αvß3 licensed intercellular αvß3-Thy1 interactions among TH2 cells, enhanced mammalian target of rapamycin (mTOR) signaling, supported differentiation and promoted IL-5/IL-13 production. In mice, αvß3 was required for efficient, allergen-driven, antigen-specific lung TH2 cell responses. Thus, αvß3-expressing TH2 cells form multicellular factories to propagate and amplify TH2 cell responses.


Assuntos
Citocinas , Células Th2 , Camundongos , Animais , Citocinas/metabolismo , Diferenciação Celular , Alérgenos , Pulmão , Mamíferos/metabolismo
2.
Nat Immunol ; 22(2): 166-178, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432227

RESUMO

Type 2 innate lymphoid cells (ILC2) contribute to immune homeostasis, protective immunity and tissue repair. Here we demonstrate that functional ILC2 cells can arise in the embryonic thymus from shared T cell precursors, preceding the emergence of CD4+CD8+ (double-positive) T cells. Thymic ILC2 cells migrated to mucosal tissues, with colonization of the intestinal lamina propria. Expression of the transcription factor RORα repressed T cell development while promoting ILC2 development in the thymus. From RNA-seq, assay for transposase-accessible chromatin sequencing (ATAC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq) data, we propose a revised transcriptional circuit to explain the co-development of T cells and ILC2 cells from common progenitors in the thymus. When Notch signaling is present, BCL11B dampens Nfil3 and Id2 expression, permitting E protein-directed T cell commitment. However, concomitant expression of RORα overrides the repression of Nfil3 and Id2 repression, allowing ID2 to repress E proteins and promote ILC2 differentiation. Thus, we demonstrate that RORα expression represents a critical checkpoint at the bifurcation of the T cell and ILC2 lineages in the embryonic thymus.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem da Célula , Imunidade Inata , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Timócitos/metabolismo , Timo/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteína 2 Inibidora de Diferenciação/genética , Proteína 2 Inibidora de Diferenciação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Técnicas de Cultura de Órgãos , Fenótipo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Timócitos/imunologia , Timo/embriologia , Timo/imunologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
3.
Immunity ; 56(7): 1468-1484.e7, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37285842

RESUMO

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.


Assuntos
Histonas , Fatores de Transcrição , Histonas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica , Células Th2 , Citocinas/metabolismo , Diferenciação Celular , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo
4.
Nature ; 632(8026): 885-892, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39112698

RESUMO

Migration and homing of immune cells are critical for immune surveillance. Trafficking is mediated by combinations of adhesion and chemokine receptors that guide immune cells, in response to chemokine signals, to specific locations within tissues and the lymphatic system to support tissue-localized immune reactions and systemic immunity1,2. Here we show that disruption of leukaemia inhibitory factor (LIF) production from group 2 innate lymphoid cells (ILC2s) prevents immune cells leaving the lungs to migrate to the lymph nodes (LNs). In the absence of LIF, viral infection leads to plasmacytoid dendritic cells (pDCs) becoming retained in the lungs where they improve tissue-localized, antiviral immunity, whereas chronic pulmonary allergen challenge leads to marked immune cell accumulation and the formation of tertiary lymphoid structures in the lung. In both cases immune cells fail to migrate to the lymphatics, leading to highly compromised LN reactions. Mechanistically, ILC2-derived LIF induces the production of the chemokine CCL21 from lymphatic endothelial cells lining the pulmonary lymphatic vessels, thus licensing the homing of CCR7+ immune cells (including dendritic cells) to LNs. Consequently, ILC2-derived LIF dictates the egress of immune cells from the lungs to regulate tissue-localized versus systemic immunity and the balance between allergen and viral responsiveness in the lungs.


Assuntos
Movimento Celular , Imunidade Inata , Fator Inibidor de Leucemia , Pulmão , Linfócitos , Animais , Feminino , Masculino , Camundongos , Alérgenos/imunologia , Movimento Celular/imunologia , Quimiocina CCL21/metabolismo , Quimiocina CCL21/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Imunidade Inata/imunologia , Fator Inibidor de Leucemia/metabolismo , Fator Inibidor de Leucemia/imunologia , Pulmão/imunologia , Pulmão/virologia , Linfonodos/citologia , Linfonodos/imunologia , Vasos Linfáticos/citologia , Vasos Linfáticos/imunologia , Vasos Linfáticos/metabolismo , Linfócitos/classificação , Linfócitos/citologia , Linfócitos/imunologia , Camundongos Endogâmicos C57BL , Receptores CCR7/metabolismo , Receptores CCR7/imunologia
5.
Immunity ; 52(5): 782-793.e5, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32272082

RESUMO

Splenic red pulp macrophages (RPMs) contribute to erythrocyte homeostasis and are required for iron recycling. Heme induces the expression of SPIC transcription factor in monocyte-derived macrophages and promotes their differentiation into RPM precursors, pre-RPMs. However, the requirements for differentiation into mature RPMs remain unknown. Here, we have demonstrated that interleukin (IL)-33 associated with erythrocytes and co-cooperated with heme to promote the generation of mature RPMs through activation of the MyD88 adaptor protein and ERK1/2 kinases downstream of the IL-33 receptor, IL1RL1. IL-33- and IL1RL1-deficient mice showed defective iron recycling and increased splenic iron deposition. Gene expression and chromatin accessibility studies revealed a role for GATA transcription factors downstream of IL-33 signaling during the development of pre-RPMs that retained full potential to differentiate into RPMs. Thus, IL-33 instructs the development of RPMs as a response to physiological erythrocyte damage with important implications to iron recycling and iron homeostasis.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/imunologia , Ferro/metabolismo , Macrófagos/imunologia , Transdução de Sinais/imunologia , Baço/metabolismo , Animais , Eritrócitos/imunologia , Eritrócitos/metabolismo , Heme/imunologia , Heme/metabolismo , Homeostase/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Macrófagos/metabolismo , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Baço/citologia
6.
Immunity ; 51(1): 104-118.e7, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31128961

RESUMO

Innate lymphoid cells (ILCs) play strategic roles in tissue homeostasis and immunity. ILCs arise from lymphoid progenitors undergoing lineage restriction and the development of specialized ILC subsets. We generated "5x polychromILC" transcription factor reporter mice to delineate ILC precursor states by revealing the multifaceted expression of key ILC-associated transcription factors (Id2, Bcl11b, Gata3, RORγt, and RORα) during ILC development in the bone marrow. This approach allowed previously unattained enrichment of rare progenitor subsets and revealed hitherto unappreciated ILC precursor heterogeneity. In vivo and in vitro assays identified precursors with potential to generate all ILC subsets and natural killer (NK) cells, and also permitted discrimination of elusive ILC3 bone marrow antecedents. Single-cell gene expression analysis identified a discrete ILC2-committed population and delineated transition states between early progenitors and a highly heterogeneous ILC1, ILC3, and NK precursor cell cluster. This diversity might facilitate greater lineage potential upon progenitor recruitment to peripheral tissues.


Assuntos
Medula Óssea/imunologia , Subpopulações de Linfócitos/fisiologia , Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Linhagem da Célula , Regulação da Expressão Gênica no Desenvolvimento , Genes Reporter , Imunidade Inata , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Análise de Célula Única , Fatores de Transcrição/genética
7.
Immunity ; 48(6): 1195-1207.e6, 2018 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-29907525

RESUMO

The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raCre/+Tnfsf4fl/fl mice). Moreover, Il7raCre/+Tnfsf4fl/fl mice failed to mount effective Th2 and Treg cell responses and corresponding adaptive type 2 pulmonary inflammation arising from Nippostrongylus brasiliensis infection or allergen exposure. Thus, the increased expression of OX40L in response to IL-33 acts as a licensing signal in the orchestration of tissue-specific adaptive type 2 immunity, without which this response fails to establish.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Glicoproteínas de Membrana/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Interleucina-33/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Camundongos , Ligante OX40
8.
Proc Natl Acad Sci U S A ; 119(49): e2203454119, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36442116

RESUMO

The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC hematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution, we have characterized bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK cell progenitors (ILC1/NKP), which we call "aceNKPs", are defined as lineage-Id2+IL-7Rα+CD25-α4ß7-NKG2A/C/E+Bcl11b-. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-γ and perforin upon IL-15 stimulation. Following reconstitution of Rag2-/-Il2rg-/- hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumor burden in a model of lung metastasis, where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.


Assuntos
Imunidade Inata , Interleucina-15 , Animais , Camundongos , Interleucina-15/genética , Células Matadoras Naturais , Perforina , Fatores de Transcrição , Proteínas Repressoras , Proteínas Supressoras de Tumor
9.
Nat Immunol ; 13(3): 229-36, 2012 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-22267218

RESUMO

Nuocytes are essential in innate type 2 immunity and contribute to the exacerbation of asthma responses. Here we found that nuocytes arose in the bone marrow and differentiated from common lymphoid progenitors, which indicates they are distinct, previously unknown members of the lymphoid lineage. Nuocytes required interleukin 7 (IL-7), IL-33 and Notch signaling for development in vitro. Pro-T cell progenitors at double-negative stage 1 (DN1) and DN2 maintained nuocyte potential in vitro, although the thymus was not essential for nuocyte development. Notably, the transcription factor RORα was critical for the development of nuocytes and their role in the expulsion of parasitic worms.


Assuntos
Diferenciação Celular , Leucócitos/imunologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Animais , Interleucina-7/imunologia , Interleucina-7/metabolismo , Leucócitos/citologia , Leucócitos/metabolismo , Camundongos , Nippostrongylus/imunologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais , Infecções por Strongylida/imunologia , Timócitos/imunologia
10.
J Cell Sci ; 127(Pt 21): 4602-19, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25189622

RESUMO

Lipid droplets are found in all cell types. Normally present at low levels in the brain, they accumulate in tumours and are associated with neurodegenerative diseases. However, little is known about the mechanisms controlling their homeostasis in the brain. We found that GRAF1a, the longest GRAF1 isoform (GRAF1 is also known as ARHGAP26), was enriched in the brains of neonates. Endogenous GRAF1a was found on lipid droplets in oleic-acid-fed primary glial cells. Exclusive localization required a GRAF1a-specific hydrophobic segment and two membrane-binding regions, a BAR and a PH domain. Overexpression of GRAF1a promoted lipid droplet clustering, inhibited droplet mobility and severely perturbed lipolysis following the chase of cells overloaded with fatty acids. Under these conditions, GRAF1a concentrated at the interface between lipid droplets. Although GRAF1-knockout mice did not show any gross abnormal phenotype, the total lipid droplet volume that accumulated in GRAF1(-/-) primary glia upon incubation with fatty acids was reduced compared to GRAF1(+/+) cells. These results provide additional insights into the mechanisms contributing to lipid droplet growth in non-adipocyte cells, and suggest that proteins with membrane sculpting BAR domains play a role in droplet homeostasis.


Assuntos
Encéfalo/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Animais , Western Blotting , Carbonatos/farmacologia , Fracionamento Celular , Células Cultivadas , Proteínas Ativadoras de GTPase/genética , Células HeLa , Humanos , Camundongos , Camundongos Mutantes , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo
11.
Nature ; 464(7293): 1367-70, 2010 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-20200518

RESUMO

Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity-responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma-consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity.


Assuntos
Imunidade Inata/imunologia , Interleucinas/imunologia , Leucócitos/imunologia , Células Th2/imunologia , Transferência Adotiva , Animais , Células Cultivadas , Interleucina-13/biossíntese , Interleucina-13/deficiência , Interleucina-13/genética , Interleucina-17/deficiência , Interleucina-17/genética , Interleucinas/biossíntese , Interleucinas/deficiência , Interleucinas/genética , Leucócitos/citologia , Leucócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nippostrongylus/imunologia , Infecções por Strongylida/imunologia
12.
Nat Commun ; 15(1): 7809, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39242588

RESUMO

Innate lymphoid cells (ILCs) are critical in maintaining tissue homeostasis, and during infection and inflammation. Here we identify, by using combinatorial reporter mice, a rare ILC progenitor (ILCP) population, resident to the small intestinal lamina propria (siLP) in adult mice. Transfer of siLP-ILCP into recipients generates group 1 ILCs (including ILC1 and NK cells), ILC2s and ILC3s within the intestinal microenvironment, but almost exclusively group 1 ILCs in the liver, lung and spleen. Single cell gene expression analysis and high dimensional spectral cytometry analysis of the siLP-ILCPs and ILC progeny indicate that the phenotype of the group 1 ILC progeny is also influenced by the tissue microenvironment. Thus, a local pool of siLP-ILCP can contribute to pan-ILC generation in the intestinal microenvironment but has more restricted potential in other tissues, with a greater propensity than bone marrow-derived ILCPs to favour ILC1 and ILC3 production. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions.


Assuntos
Imunidade Inata , Mucosa Intestinal , Células Progenitoras Linfoides , Camundongos Endogâmicos C57BL , Animais , Camundongos , Mucosa Intestinal/imunologia , Mucosa Intestinal/citologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/imunologia , Microambiente Celular/imunologia , Linfócitos/imunologia , Intestino Delgado/imunologia , Intestino Delgado/citologia , Feminino , Masculino
13.
Science ; 384(6703): eadl0370, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38935708

RESUMO

Innate lymphoid cells (ILCs) and adaptive T lymphocytes promote tissue homeostasis and protective immune responses. Their production depends on the transcription factor GATA3, which is further elevated specifically in ILC2s and T helper 2 cells to drive type-2 immunity during tissue repair, allergic disorders, and anti-helminth immunity. The control of this crucial up-regulation is poorly understood. Using CRISPR screens in ILCs we identified previously unappreciated myocyte-specific enhancer factor 2d (Mef2d)-mediated regulation of GATA3-dependent type-2 lymphocyte differentiation. Mef2d-deletion from ILC2s and/or T cells specifically protected against an allergen lung challenge. Mef2d repressed Regnase-1 endonuclease expression to enhance IL-33 receptor production and IL-33 signaling and acted downstream of calcium-mediated signaling to translocate NFAT1 to the nucleus to promote type-2 cytokine-mediated immunity.


Assuntos
Fator de Transcrição GATA3 , Imunidade Inata , Interleucina-33 , Fatores de Transcrição MEF2 , Fatores de Transcrição NFATC , Pneumonia , Células Th2 , Animais , Camundongos , Fatores de Transcrição MEF2/metabolismo , Fatores de Transcrição MEF2/genética , Células Th2/imunologia , Interleucina-33/metabolismo , Fatores de Transcrição NFATC/metabolismo , Pneumonia/imunologia , Fator de Transcrição GATA3/metabolismo , Fator de Transcrição GATA3/genética , Camundongos Endogâmicos C57BL , Diferenciação Celular , Sinalização do Cálcio , Hipersensibilidade/imunologia , Pulmão/imunologia , Alérgenos/imunologia , Linfócitos/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1
14.
J Exp Med ; 203(4): 1105-16, 2006 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-16606668

RESUMO

Type 2 immunity, which involves coordinated regulation of innate and adaptive immune responses, can protect against helminth parasite infection, but may lead to allergy and asthma after inappropriate activation. We demonstrate that il25(-/-) mice display inefficient Nippostrongylus brasiliensis expulsion and delayed cytokine production by T helper 2 cells. We further establish a key role for interleukin (IL)-25 in regulating a novel population of IL-4-, IL-5-, IL-13-producing non-B/non-T (NBNT), c-kit+, FcepsilonR1- cells during helminth infection. A deficit in this population in il25(-/-) mice correlates with inefficient N. brasiliensis expulsion. In contrast, administration of recombinant IL-25 in vivo induces the appearance of NBNT, c-kit+, FcepsilonR1- cells and leads to rapid worm expulsion that is T and B cell independent, but type 2 cytokine dependent. We demonstrate that these IL-25-regulated cells appear rapidly in the draining lymph nodes, implicating them as a source of type 2 cytokines during initiation of worm expulsion.


Assuntos
Linfócitos B/citologia , Basófilos/metabolismo , Interleucinas/fisiologia , Nippostrongylus/imunologia , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Linfócitos T/citologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Citocinas/biossíntese , Citocinas/classificação , Interleucina-13/biossíntese , Interleucina-13/deficiência , Interleucina-13/genética , Interleucina-4/biossíntese , Interleucina-4/deficiência , Interleucina-4/genética , Interleucina-5/biossíntese , Interleucina-5/deficiência , Interleucina-5/genética , Interleucinas/administração & dosagem , Interleucinas/deficiência , Interleucinas/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores de IgE/deficiência , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
15.
Sci Immunol ; 7(69): eabn3286, 2022 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-35275754

RESUMO

Therapeutic interventions used for cancer treatment provoke thymus damage and limit the recovery of protective immunity. Here, we show that eosinophils are an essential part of an intrathymic type 2 immune network that enables thymus recovery after ablative therapy. Within hours of damage, the thymus undergoes CCR3-dependent colonization by peripheral eosinophils, which reestablishes the epithelial microenvironments that control thymopoiesis. Eosinophil regulation of thymus regeneration occurs via the concerted action of NKT cells that trigger CCL11 production via IL4 receptor signaling in thymic stroma, and ILC2 that represent an intrathymic source of IL5, a cytokine that therapeutically boosts thymus regeneration after damage. Collectively, our findings identify an intrathymic network composed of multiple innate immune cells that restores thymus function during reestablishment of the adaptive immune system.


Assuntos
Eosinófilos , Regeneração , Timo , Imunidade Adaptativa , Citocinas , Eosinófilos/imunologia , Interleucina-5/imunologia , Linfócitos , Timo/imunologia
16.
Sci Immunol ; 7(72): eabn0175, 2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35658010

RESUMO

Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33-activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25-activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R-expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-γ (IFN-γ)-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Interleucina-33 , Células Supressoras Mieloides , Carcinogênese , Humanos , Imunidade Inata , Interleucina-17 , Interleucina-33/genética , Linfócitos , Mutação , Microambiente Tumoral
17.
Front Immunol ; 12: 711907, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34484215

RESUMO

Group 2 innate lymphoid cells (ILC2s) are early effectors of mucosal type 2 immunity, producing cytokines such as interleukin (IL)-13 to mediate responses to helminth infection and allergen-induced inflammation. ILC2s are also present in lymph nodes (LNs) and can express molecules required for antigen presentation, but to date there are limited data on their dynamic behaviour. We used a CD2/IL-13 dual fluorescent reporter mouse for in vivo imaging of ILC2s and Th2 T cells in real time following a type 2 priming helminth infection or egg injection. After helminth challenge, we found that ILC2s were the main source of IL-13 in lymphoid organs (Peyer's patches and peripheral LNs), and were located in T cell areas. Intravital imaging demonstrated an increase in IL-13+ ILC2 size and movement following helminth infection, but reduced duration of interactions with T cells compared with those in homeostasis. In contrast, in the intestinal mucosa, we observed an increase in ILC2-T cell interactions post-infection, including some of prolonged duration, as well as increased IL-13+ ILC2 movement. These data suggest that ILC2 activation enhances cell motility, with the potential to increase the area of distribution of cytokines to optimise the early generation of type 2 responses. The prolonged ILC2 interactions with T cells within the intestinal mucosa are consistent with the conclusion that contact-based T cell activation may occur within inflamed tissues rather than lymphoid organs. Our findings have important implications for our understanding of the in vivo biology of ILC2s and the way in which these cells facilitate adaptive immune responses.


Assuntos
Enteropatias Parasitárias/imunologia , Subpopulações de Linfócitos/imunologia , Nippostrongylus , Esquistossomose mansoni/imunologia , Infecções por Strongylida/imunologia , Células Th2/imunologia , Animais , Genes Reporter , Interleucina-13/análise , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Intestino Delgado/parasitologia , Microscopia Intravital , Contagem de Linfócitos , Subpopulações de Linfócitos/química , Camundongos , Especificidade de Órgãos , Organismos Livres de Patógenos Específicos , Células Th2/química
18.
Nat Metab ; 3(9): 1150-1162, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34531575

RESUMO

Macrophages exhibit a spectrum of activation states ranging from classical to alternative activation1. Alternatively, activated macrophages are involved in diverse pathophysiological processes such as confining tissue parasites2, improving insulin sensitivity3 or promoting an immune-tolerant microenvironment that facilitates tumour growth and metastasis4. Recently, the metabolic regulation of macrophage function has come into focus as both the classical and alternative activation programmes require specific regulated metabolic reprogramming5. While most of the studies regarding immunometabolism have focussed on the catabolic pathways activated to provide energy, little is known about the anabolic pathways mediating macrophage alternative activation. In this study, we show that the anabolic transcription factor sterol regulatory element binding protein 1 (SREBP1) is activated in response to the canonical T helper 2 cell cytokine interleukin-4 to trigger the de novo lipogenesis (DNL) programme, as a necessary step for macrophage alternative activation. Mechanistically, DNL consumes NADPH, partitioning it away from cellular antioxidant defences and raising reactive oxygen species levels. Reactive oxygen species serves as a second messenger, signalling sufficient DNL, and promoting macrophage alternative activation. The pathophysiological relevance of this mechanism is validated by showing that SREBP1/DNL is essential for macrophage alternative activation in vivo in a helminth infection model.


Assuntos
Antioxidantes/metabolismo , Ácidos Graxos/biossíntese , Macrófagos/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Dexametasona/farmacologia , Humanos , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Nippostrongylus/isolamento & purificação , Nippostrongylus/patogenicidade , Células RAW 264.7 , Análise de Sequência de RNA/métodos , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Regulação para Cima
19.
Mucosal Immunol ; 14(1): 26-37, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32457448

RESUMO

Type-2 immunity is characterised by interleukin (IL)-4, IL-5 and IL-13, eosinophilia, mucus production, IgE, and alternatively activated macrophages (AAM). However, despite the lack of neutrophil chemoattractants such as CXCL1, neutrophils, a feature of type-1 immunity, are observed in type-2 responses. Consequently, alternative mechanisms must exist to ensure that neutrophils can contribute to type-2 immune reactions without escalation of deleterious inflammation. We now demonstrate that type-2 immune-associated neutrophil infiltration is regulated by the mouse RNase A homologue, eosinophil-associated ribonuclease 11 (Ear11), which is secreted by AAM downstream of IL-25-stimulated ILC2. Transgenic overexpression of Ear11 resulted in tissue neutrophilia, whereas Ear11-deficient mice have fewer resting tissue neutrophils, whilst other type-2 immune responses are not impaired. Notably, administration of recombinant mouse Ear11 increases neutrophil motility and recruitment. Thus, Ear11 helps maintain tissue neutrophils at homoeostasis and during type-2 reactions when chemokine-producing classically activated macrophages are infrequently elicited.


Assuntos
Imunidade Inata , Linfócitos/fisiologia , Ativação de Macrófagos/imunologia , Macrófagos/fisiologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/fisiologia , Ribonucleases/biossíntese , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Imunomodulação , Imunofenotipagem , Interleucina-13/biossíntese , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Transgênicos , Ribonucleases/genética
20.
J Exp Med ; 200(11): 1383-93, 2004 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-15583012

RESUMO

Rapid clearance of pathogens is essential for successful control of pyogenic bacterial infection. Previous experiments have shown that antibody to specific intracellular adhesion molecule-grabbing nonintegrin (SIGN)-R1 inhibits uptake of capsular polysaccharide by marginal zone macrophages, suggesting a role for SIGN-R1 in this process. We now demonstrate that mice lacking SIGN-R1 (a mouse homologue of human dendritic cell-SIGN receptor) are significantly more susceptible to Streptococcus pneumoniae infection and fail to clear S. pneumoniae from the circulation. Marginal zone and peritoneal macrophages show impaired bacterial recognition associated with an inability to bind T-independent type 2 antigens such as dextran. Our work represents the first evidence for a protective in vivo role for a SIGN family molecule.


Assuntos
Antígenos CD/fisiologia , Lectinas Tipo C/fisiologia , Infecções Pneumocócicas/imunologia , Animais , Anticorpos Antibacterianos/sangue , Antígenos CD/genética , Moléculas de Adesão Celular , Clonagem Molecular , Dextranos/metabolismo , Feminino , Imunidade Inata , Lectinas Tipo C/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Células NIH 3T3 , Receptores de Superfície Celular , Streptococcus pneumoniae/imunologia
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