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1.
Nat Immunol ; 25(1): 77-87, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38049581

RESUMEN

Intestinal intraepithelial lymphocytes (IELs) exhibit prompt innate-like responses to microenvironmental cues and require strict control of effector functions. Here we showed that Aiolos, an Ikaros zinc-finger family member encoded by Ikzf3, acted as a regulator of IEL activation. Ikzf3-/- CD8αα+ IELs had elevated expression of NK receptors, cytotoxic enzymes, cytokines and chemokines. Single-cell RNA sequencing of Ikzf3-/- and Ikzf3+/+ IELs showed an amplified effector machinery in Ikzf3-/- CD8αα+ IELs compared to Ikzf3+/+ counterparts. Ikzf3-/- CD8αα+ IELs had increased responsiveness to interleukin-15, which explained a substantial part, but not all, of the observed phenotypes. Aiolos binding sites were close to those for the transcription factors STAT5 and RUNX, which promote interleukin-15 signaling and cytolytic programs, and Ikzf3 deficiency partially increased chromatin accessibility and histone acetylation in these regions. Ikzf3 deficiency in mice enhanced susceptibility to colitis, underscoring the relevance of Aiolos in regulating the effector function in IELs.


Asunto(s)
Linfocitos Intraepiteliales , Factores de Transcripción , Animales , Ratones , Antígenos CD8/metabolismo , Interleucina-15/metabolismo , Mucosa Intestinal/metabolismo , Linfocitos Intraepiteliales/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
2.
Nat Immunol ; 23(4): 619-631, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35332328

RESUMEN

Innate lymphocytes encompass a diverse array of phenotypic identities with specialized functions. DNA methylation and hydroxymethylation are essential for epigenetic fidelity and fate commitment. The landscapes of these modifications are unknown in innate lymphocytes. Here, we characterized the whole-genome distribution of methyl-CpG and 5-hydroxymethylcytosine (5hmC) in mouse innate lymphoid cell 3 (ILC3), ILC2 and natural killer (NK) cells. We identified differentially methylated regions (DMRs) and differentially hydroxymethylated regions (DHMRs) between ILC and NK cell subsets and correlated them with transcriptional signatures. We associated lineage-determining transcription factors (LDTFs) with demethylation and demonstrated unique patterns of DNA methylation/hydroxymethylation in relationship to open chromatin regions (OCRs), histone modifications and TF-binding sites. We further identified an association between hydroxymethylation and NK cell superenhancers (SEs). Using mice lacking the DNA hydroxymethylase TET2, we showed the requirement for TET2 in optimal production of hallmark cytokines by ILC3s and interleukin-17A (IL-17A) by inflammatory ILC2s. These findings provide a powerful resource for studying innate lymphocyte epigenetic regulation and decode the regulatory logic governing their identity.


Asunto(s)
Metilación de ADN , Inmunidad Innata , Animales , Cromatina/genética , Epigénesis Genética , Inmunidad Innata/genética , Células Asesinas Naturales , Linfocitos , Ratones
3.
Immunity ; 57(7): 1567-1585.e5, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38821051

RESUMEN

Conventional dendritic cells (cDC) are antigen-presenting cells comprising cDC1 and cDC2, responsible for priming naive CD8+ and CD4+ T cells, respectively. Recent studies have unveiled cDC2 heterogeneity and identified various cDC2 progenitors beyond the common DC progenitor (CDP), hinting at distinct cDC2 lineages. By generating Cd300ciCre-hCD2R26tdTomato reporter mice, we identified a bone marrow pro-cDC2 progenitor exclusively generating cDC2 in vitro and in vivo. Single-cell analyses and multiparametric flow cytometry demonstrated that pro-cDC2 encompasses myeloid-derived pre-cDC2 and lymphoid-derived plasmacytoid DC (pDC)-like precursors differentiating into a transcriptionally convergent cDC2 phenotype. Cd300c-traced cDC2 had distinct transcriptomic profiles, phenotypes, and tissue distributions compared with Ms4a3CreR26tdTomato lineage-traced DC3, a monocyte-DC progenitor (MDP)-derived subset that bypasses CDP. Mice with reduced Cd300c-traced cDC2 showed impaired humoral responses to T cell-dependent antigens. We conclude that progenitors of distinct lineages shape the diversity of mature cDC2 across tissues. Thus, ontogenesis may impact tissue immune responses.


Asunto(s)
Diferenciación Celular , Linaje de la Célula , Células Dendríticas , Animales , Células Dendríticas/inmunología , Ratones , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Análisis de la Célula Individual , Células Madre/citología , Células Madre/inmunología , Células Madre/metabolismo , Ratones Transgénicos
4.
Immunity ; 56(4): 797-812.e4, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-36801011

RESUMEN

The aryl-hydrocarbon receptor (AHR) is a ligand-activated transcription factor that buoys intestinal immune responses. AHR induces its own negative regulator, the AHR repressor (AHRR). Here, we show that AHRR is vital to sustaining intestinal intraepithelial lymphocytes (IELs). AHRR deficiency reduced IEL representation in a cell-intrinsic fashion. Single-cell RNA sequencing revealed an oxidative stress profile in Ahrr-/- IELs. AHRR deficiency unleashed AHR-induced expression of CYP1A1, a monooxygenase that generates reactive oxygen species, increasing redox imbalance, lipid peroxidation, and ferroptosis in Ahrr-/- IELs. Dietary supplementation with selenium or vitamin E to restore redox homeostasis rescued Ahrr-/- IELs. Loss of IELs in Ahrr-/- mice caused susceptibility to Clostridium difficile infection and dextran sodium-sulfate-induced colitis. Inflamed tissue of inflammatory bowel disease patients showed reduced Ahrr expression that may contribute to disease. We conclude that AHR signaling must be tightly regulated to prevent oxidative stress and ferroptosis of IELs and to preserve intestinal immune responses.


Asunto(s)
Ferroptosis , Linfocitos Intraepiteliales , Animales , Ratones , Linfocitos Intraepiteliales/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Estrés Oxidativo , Hidrocarburos
5.
Proc Natl Acad Sci U S A ; 120(52): e2318710120, 2023 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-38109523

RESUMEN

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt+ MHCII+ type 3 innate lymphoid cells (ILC3) have also been implicated in the instruction of microbiota-specific Tregs. While RORγt+ APCs have been actively investigated in mice, the identity and function of these cell subsets in humans remain elusive. Herein, we identify a rare subset of RORγt+ cells with dendritic cell (DC) features through integrated single-cell RNA sequencing and single-cell ATAC sequencing. These cells, which we term RORγt+ DC-like cells (R-DC-like), exhibit DC morphology, express the MHC class II machinery, and are distinct from all previously reported DC and ILC3 subsets, but share transcriptional and epigenetic similarities with DC2 and ILC3. We have developed procedures to isolate and expand them in vitro, enabling their functional characterization. R-DC-like cells proliferate in vitro, continue to express RORγt, and differentiate into CD1c+ DC2-like cells. They stimulate the proliferation of allogeneic T cells. The identification of human R-DC-like cells with proliferative potential and plasticity toward CD1c+ DC2-like cells will prompt further investigation into their impact on immune homeostasis, inflammation, and autoimmunity.


Asunto(s)
Inmunidad Innata , Linfocitos , Humanos , Ratones , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Inflamación/metabolismo , Células Dendríticas
6.
Proc Natl Acad Sci U S A ; 119(45): e2214900119, 2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36279426

RESUMEN

Group 3 innate lymphoid cells (ILC3s) are RORγT+ lymphocytes that are predominately enriched in mucosal tissues and produce IL-22 and IL-17A. They are the innate counterparts of Th17 cells. While Th17 lymphocytes utilize unique metabolic pathways in their differentiation program, it is unknown whether ILC3s make similar metabolic adaptations. We employed single-cell RNA sequencing and metabolomic profiling of intestinal ILC subsets to identify an enrichment of polyamine biosynthesis in ILC3s, converging on the rate-limiting enzyme ornithine decarboxylase (ODC1). In vitro and in vivo studies demonstrated that exogenous supplementation with the polyamine putrescine or its biosynthetic substrate, ornithine, enhanced ILC3 production of IL-22. Conditional deletion of ODC1 in ILC3s impaired mouse antibacterial defense against Citrobacter rodentium infection, which was associated with a decrease in anti-microbial peptide production by the intestinal epithelium. Furthermore, in a model of anti-CD40 colitis, deficiency of ODC1 in ILC3s markedly reduced the production of IL-22 and severity of inflammatory colitis. We conclude that ILC3-intrinsic polyamine biosynthesis facilitates efficient defense against enteric pathogens as well as exacerbates autoimmune colitis, thus representing an attractive target to modulate ILC3 function in intestinal disease.


Asunto(s)
Colitis , Infecciones por Enterobacteriaceae , Ratones , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Interleucina-17 , Ornitina Descarboxilasa/genética , Inmunidad Innata , Putrescina , Colitis/genética , Infecciones por Enterobacteriaceae/genética , Células Th17/metabolismo , Ornitina , Antibacterianos , Interleucina-22
7.
Proc Natl Acad Sci U S A ; 118(50)2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34880136

RESUMEN

Identification of type 1 innate lymphoid cells (ILC1s) has been problematic. The transcription factor Hobit encoded by Zfp683 has been proposed as a major driver of ILC1 programs. Using Zfp683 reporter mice, we showed that correlation of Hobit expression with ILC1s is tissue- and context-dependent. In liver and intestinal mucosa, Zfp683 expression correlated well with ILC1s; in salivary glands, Zfp683 was coexpressed with the natural killer (NK) master transcription factors Eomes and TCF1 in a unique cell population, which we call ILC1-like NK cells; during viral infection, Zfp683 was induced in conventional NK cells of spleen and liver. The impact of Zfp683 deletion on ILC1s and NK cells was also multifaceted, including a marked decrease in granzyme- and interferon-gamma (IFNγ)-producing ILC1s in the liver, slightly fewer ILC1s and more Eomes+ TCF1+ ILC1-like NK cells in salivary glands, and only reduced production of granzyme B by ILC1 in the intestinal mucosa. NK cell-mediated control of viral infection was unaffected. We conclude that Hobit has two major impacts on ILC1s: It sustains liver ILC1 numbers, while promoting ILC1 functional maturation in other tissues by controlling TCF1, Eomes, and granzyme expression.


Asunto(s)
Inmunidad Celular/fisiología , Inmunidad Innata/fisiología , Subgrupos Linfocitarios/clasificación , Subgrupos Linfocitarios/fisiología , Proteínas de Dominio T Box/metabolismo , Factores de Transcripción/metabolismo , Animales , Antígenos CD , Biomarcadores , Eliminación de Gen , Regulación de la Expresión Génica/fisiología , Granzimas/genética , Granzimas/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Hígado/metabolismo , Proteínas de la Membrana/genética , Ratones , ARN Citoplasmático Pequeño/genética , ARN Citoplasmático Pequeño/metabolismo , RNA-Seq , Proteínas de Dominio T Box/genética , Factores de Transcripción/genética
8.
J Gen Virol ; 103(11)2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36409610

RESUMEN

Human cytomegalovirus is responsible for morbidity and mortality in immune compromised patients and is the leading viral cause of congenital infection. Virus-encoded microRNAs (miRNAs) represent interesting targets for novel antiviral agents. While many cellular targets that augment productive infection have been identified in recent years, regulation of viral genes such as the major viral immediate early protein 72 (IE72) by hcmv-miR-UL112-1 may contribute to both the establishment and the maintenance of latent infection. We employed photoactivated ribonucleotide-enhanced individual nucleotide resolution crosslinking (PAR-iCLIP) to identify murine cytomegalovirus (MCMV) miRNA targets during lytic infection. While the PAR-iCLIP data were of insufficient quality to obtain a comprehensive list of cellular and viral miRNA targets, the most prominent PAR-iCLIP peak in the MCMV genome mapped to the 3' untranslated region of the major viral immediate early 3 (ie3) transcript. We show that this results from two closely positioned binding sites for the abundant MCMV miRNAs miR-M23-2-3p and miR-m01-2-3p. Their pre-expression significantly impaired viral plaque formation. However, mutation of the respective binding sites did not alter viral fitness during acute or subacute infection in vivo. Furthermore, no differences in the induction of virus-specific CD8+ T cells were observed. Future studies will probably need to go beyond studying immunocompetent laboratory mice housed in pathogen-free conditions to reveal the functional relevance of viral miRNA-mediated regulation of key viral immediate early genes.


Asunto(s)
MicroARNs , Muromegalovirus , Humanos , Ratones , Animales , Muromegalovirus/genética , Genes Inmediatos-Precoces , Linfocitos T CD8-positivos/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Citomegalovirus/genética , Regiones no Traducidas 3'
9.
Immunity ; 34(4): 458-60, 2011 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-21511179

RESUMEN

NK cells play a key role in the control of ectromelia virus. In this issue of Immunity, Fang et al. (2011) demonstrate that the deletion of CD94 abolishes resistance to mousepox infection.

10.
J Immunol ; 199(5): 1567-1571, 2017 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-28760883

RESUMEN

NK cells play a critical role in host defense against viruses. In this study, we investigated the role of NKG2D in the expansion of NK cells after mouse CMV (MCMV) infection. Wild-type and NKG2D-deficient (Klrk1-/- ) Ly49H+ NK cells proliferated robustly when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naive NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with DAP10 and DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H- NK cells when mice were infected with these MCMV strains, likely because NKG2D-S was only transiently expressed postinfection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of the NKG2D-DAP12 complex.


Asunto(s)
Infecciones por Herpesviridae/inmunología , Células Asesinas Naturales/inmunología , Muromegalovirus/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proliferación Celular , Células Cultivadas , Inmunidad Innata , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Unión Proteica , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Transducción de Señal
11.
Eur J Immunol ; 47(9): 1443-1456, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28643847

RESUMEN

NKp46/NCR1 is an activating NK-cell receptor implicated in the control of various viral and bacterial infections. Recent findings also suggest that it plays a role in shaping the adaptive immune response to pathogens. Using NCR1-deficient (NCR1gfp/gfp ) mice, we provide evidence for the role of NCR1 in antibody response to mouse cytomegalovirus infection (MCMV). The absence of NCR1 resulted in impaired maturation, function and NK-cell migration to regional lymph nodes. In addition, CD4+ T-cell activation and follicular helper T-cell (Tfh) generation were reduced, leading to inferior germinal center (GC) B-cell maturation. As a consequence, NCR1gfp/gfp mice produced lower amounts of MCMV-specific antibodies upon infection, which correlated with lower number of virus-specific antibody secreting cells in analyzed lymph nodes.


Asunto(s)
Antígenos Ly/metabolismo , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/inmunología , Centro Germinal/inmunología , Infecciones por Herpesviridae/inmunología , Células Asesinas Naturales/inmunología , Muromegalovirus/inmunología , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Animales , Anticuerpos Antivirales/sangre , Antígenos Ly/genética , Diferenciación Celular , Movimiento Celular , Células Cultivadas , Inmunidad Humoral , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptor 1 Gatillante de la Citotoxidad Natural/genética
12.
Eur J Immunol ; 47(8): 1354-1367, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28612942

RESUMEN

Designing CD8+ T-cell vaccines, which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show the robust potential of cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8+ T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ, delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1. CMV vector expressing RAE-1γ potentiated expansion of KLRG1+ CD8+ T cells with enhanced effector properties. This vaccination was even more efficient in neonatal mice, resulting in the expansion and long-term maintenance of epitope-specific CD8+ T cells conferring robust resistance against tumor challenge. Our data show that immunomodulation of CD8+ T-cell responses promoted by herpesvirus expressing a ligand for NKG2D receptor can provide a powerful platform for the prevention and treatment of CD8+ T-cell sensitive tumors.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Citomegalovirus/genética , Proteínas de la Membrana/genética , Neoplasias/inmunología , Animales , Animales Recién Nacidos , Citomegalovirus/inmunología , Modelos Animales de Enfermedad , Epítopos de Linfocito T/inmunología , Femenino , Vectores Genéticos , Humanos , Inmunomodulación , Inmunoterapia/métodos , Células Asesinas Naturales/inmunología , Lectinas Tipo C , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Proteínas de la Membrana/inmunología , Ratones , Neoplasias/prevención & control , Neoplasias/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología
13.
Proc Natl Acad Sci U S A ; 110(41): 16550-5, 2013 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-24052528

RESUMEN

Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cell-based vaccines.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Citomegalovirus/inmunología , Vectores Genéticos/inmunología , Evasión Inmune/inmunología , Proteínas de la Membrana/metabolismo , Vacunas Sintéticas/inmunología , Animales , Citomegalovirus/genética , Citometría de Flujo , Vectores Genéticos/genética , Listeria monocytogenes/inmunología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Estadísticas no Paramétricas
14.
PLoS Pathog ; 9(9): e1003611, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24086132

RESUMEN

Major gaps in our knowledge of pathogen genes and how these gene products interact with host gene products to cause disease represent a major obstacle to progress in vaccine and antiviral drug development for the herpesviruses. To begin to bridge these gaps, we conducted a dual analysis of Murine Cytomegalovirus (MCMV) and host cell transcriptomes during lytic infection. We analyzed the MCMV transcriptome during lytic infection using both classical cDNA cloning and sequencing of viral transcripts and next generation sequencing of transcripts (RNA-Seq). We also investigated the host transcriptome using RNA-Seq combined with differential gene expression analysis, biological pathway analysis, and gene ontology analysis. We identify numerous novel spliced and unspliced transcripts of MCMV. Unexpectedly, the most abundantly transcribed viral genes are of unknown function. We found that the most abundant viral transcript, recently identified as a noncoding RNA regulating cellular microRNAs, also codes for a novel protein. To our knowledge, this is the first viral transcript that functions both as a noncoding RNA and an mRNA. We also report that lytic infection elicits a profound cellular response in fibroblasts. Highly upregulated and induced host genes included those involved in inflammation and immunity, but also many unexpected transcription factors and host genes related to development and differentiation. Many top downregulated and repressed genes are associated with functions whose roles in infection are obscure, including host long intergenic noncoding RNAs, antisense RNAs or small nucleolar RNAs. Correspondingly, many differentially expressed genes cluster in biological pathways that may shed new light on cytomegalovirus pathogenesis. Together, these findings provide new insights into the molecular warfare at the virus-host interface and suggest new areas of research to advance the understanding and treatment of cytomegalovirus-associated diseases.


Asunto(s)
Infecciones por Herpesviridae/metabolismo , Interacciones Huésped-Patógeno/fisiología , MicroARNs/biosíntesis , Muromegalovirus/fisiología , Factores de Transcripción/biosíntesis , Transcriptoma , Regulación hacia Arriba , Animales , Línea Celular Transformada , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/virología , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/patología , Ratones , MicroARNs/genética , Factores de Transcripción/genética
15.
PLoS Pathog ; 9(7): e1003493, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23935483

RESUMEN

Human cytomegalovirus (HCMV) forms two gH/gL glycoprotein complexes, gH/gL/gO and gH/gL/pUL(128,130,131A), which determine the tropism, the entry pathways and the mode of spread of the virus. For murine cytomegalovirus (MCMV), which serves as a model for HCMV, a gH/gL/gO complex functionally homologous to the HCMV gH/gL/gO complex has been described. Knock-out of MCMV gO does impair, but not abolish, virus spread indicating that also MCMV might form an alternative gH/gL complex. Here, we show that the MCMV CC chemokine MCK-2 forms a complex with the glycoprotein gH, a complex which is incorporated into the virion. We could additionally show that mutants lacking both, gO and MCK-2 are not able to produce infectious virus. Trans-complementation of these double mutants with either gO or MCK-2 showed that both proteins can promote infection of host cells, although through different entry pathways. MCK-2 has been extensively studied in vivo by others. It has been shown to be involved in attracting cells for virus dissemination and in regulating antiviral host responses. We now show that MCK-2, by forming a complex with gH, strongly promotes infection of macrophages in vitro and in vivo. Thus, MCK-2 may play a dual role in MCMV infection, as a chemokine regulating the host response and attracting specific target cells and as part of a glycoprotein complex promoting entry into cells crucial for virus dissemination.


Asunto(s)
Quimiocinas CC/metabolismo , Infecciones por Herpesviridae/inmunología , Inmunidad Innata , Macrófagos/inmunología , Muromegalovirus/fisiología , Proteínas del Envoltorio Viral/metabolismo , Proteínas Virales/metabolismo , Internalización del Virus , Animales , Línea Celular , Células Cultivadas , Quimiocinas CC/química , Quimiocinas CC/genética , Femenino , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/patología , Infecciones por Herpesviridae/virología , Hígado/inmunología , Hígado/patología , Hígado/virología , Macrófagos/patología , Macrófagos/virología , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/patología , Macrófagos Peritoneales/virología , Ratones , Ratones Endogámicos BALB C , Muromegalovirus/inmunología , Mutación , Multimerización de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Organismos Libres de Patógenos Específicos , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Proteínas Virales/química , Proteínas Virales/genética , Virión/inmunología , Virión/fisiología
16.
J Exp Med ; 221(3)2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38197946

RESUMEN

Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using an scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the prosurvival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment, and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells.


Asunto(s)
Inmunidad Innata , Proteínas Proto-Oncogénicas c-akt , Células Asesinas Naturales , Homeostasis
17.
Mucosal Immunol ; 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38992433

RESUMEN

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity.

18.
Sci Transl Med ; 16(741): eadj9052, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38569016

RESUMEN

Microglia help limit the progression of Alzheimer's disease (AD) by constraining amyloid-ß (Aß) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aß and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aß plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aß load, mitigated some Aß-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.


Asunto(s)
Enfermedad de Alzheimer , Microglía , Humanos , Ratones , Animales , Microglía/metabolismo , Anticuerpos/metabolismo , Receptores de Superficie Celular/metabolismo , Amiloide/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Apolipoproteínas E , Leucocitos/metabolismo , Ratones Transgénicos , Glicoproteínas de Membrana/metabolismo , Receptores Inmunológicos/metabolismo
19.
Dev Cell ; 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38942017

RESUMEN

Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease.

20.
Sci Immunol ; 9(95): eadi5374, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38758808

RESUMEN

The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti-programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti-PD-1. Here, we found that anti-PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti-PD-1-mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti-PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.


Asunto(s)
Microbioma Gastrointestinal , Inmunoterapia , Macrófagos , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1 , Receptores Inmunológicos , Animales , Receptores Inmunológicos/inmunología , Receptores Inmunológicos/deficiencia , Receptores Inmunológicos/genética , Ratones , Microbioma Gastrointestinal/inmunología , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Macrófagos/inmunología , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones Noqueados , Femenino , Intestinos/inmunología
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