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1.
Nat Immunol ; 22(10): 1256-1267, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34462601

RESUMO

Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit+CD127hiTCF-1hi early differentiation stages of T-bet+ ILC1s. These cells were present across different organs and had the potential to mature toward CD127intTCF-1int and CD127-TCF-1- ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.


Assuntos
Diferenciação Celular/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Fatores de Transcrição/imunologia , Animais , Feminino , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/imunologia , Linfócitos T/imunologia
2.
Immunity ; 57(1): 124-140.e7, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38157853

RESUMO

Natural killer (NK) cells are present in the circulation and can also be found residing in tissues, and these populations exhibit distinct developmental requirements and are thought to differ in terms of ontogeny. Here, we investigate whether circulating conventional NK (cNK) cells can develop into long-lived tissue-resident NK (trNK) cells following acute infections. We found that viral and bacterial infections of the skin triggered the recruitment of cNK cells and their differentiation into Tcf1hiCD69hi trNK cells that share transcriptional similarity with CD56brightTCF1hi NK cells in human tissues. Skin trNK cells arose from interferon (IFN)-γ-producing effector cells and required restricted expression of the transcriptional regulator Blimp1 to optimize Tcf1-dependent trNK cell formation. Upon secondary infection, trNK cells rapidly gained effector function and mediated an accelerated NK cell response. Thus, cNK cells redistribute and permanently position at sites of previous infection via a mechanism promoting tissue residency that is distinct from Hobit-dependent developmental paths of NK cells and ILC1 seeding tissues during ontogeny.


Assuntos
Coinfecção , Humanos , Células Matadoras Naturais/metabolismo , Diferenciação Celular
3.
Immunity ; 53(4): 775-792.e9, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33002412

RESUMO

Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Células Progenitoras Linfoides/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-18/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Transdução de Sinais/imunologia , Análise de Célula Única/métodos , Fator 1 de Transcrição de Linfócitos T/imunologia , Fatores de Transcrição/imunologia
4.
Nature ; 610(7933): 752-760, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36070798

RESUMO

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1-4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5-8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I-TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-ß-activating integrin αvß8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.


Assuntos
Células Apresentadoras de Antígenos , Células Dendríticas , Células Epiteliais , Microbioma Gastrointestinal , Tolerância Imunológica , Linfócitos T Reguladores , Timo , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Timo/citologia , Timo/imunologia , Fator de Crescimento Transformador beta/imunologia , Células Apresentadoras de Antígenos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Linfonodos/imunologia
5.
Immunity ; 47(1): 8-10, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28723555

RESUMO

T cell homeostasis critically depends on interleukin-7 (IL-7). In this issue of Immunity, Martin et al. (2017) provide evidence that IL-7 availability is regulated through a "cytokine sink" involving innate lymphoid cells that compete for and consume IL-7 and thereby restrict T cell homeostasis in lymphoid organs.


Assuntos
Imunidade Inata/imunologia , Linfócitos T , Citocinas , Humanos , Interleucina-7 , Linfócitos/imunologia
6.
Eur J Immunol ; : e2451043, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-39348088

RESUMO

Macrophage activation syndrome (MAS) exemplifies a severe cytokine storm disorder with liver inflammation. In the liver, classical natural killer (cNK) cells and liver-resident type 1 innate lymphoid cells (ILC1s) dominate the ILC population. Thus far, research has primarily focused on the corresponding role of cNK cells. Considering the liver inflammation and cytokine storm in MAS, liver-resident ILC1s represent an interesting population to explore due to their rapid cytokine production upon environmental triggers. By utilizing a Toll-like receptor (TLR)9- and TLR3:4-triggered MAS model, we showed that ILC1s highly produce IFN-γ and TNF-α. However, activated ILC1s undergo apoptosis and are strongly reduced in numbers, while cNK cells resist inflammation-induced apoptosis. Signs of mitochondrial stress suggest that this ILC1 apoptosis may be driven by inflammation-induced mitochondrial impairment. To study whether early induction of highly cytokine-producing ILC1s influences MAS development, we used Hobit KO mice due to their paucity of liver ILC1s but unaffected cNK cell numbers. Nevertheless, neither the severity of MAS features nor the total inflammatory cytokine levels were affected in these Hobit KO mice, indicating that ILC1s are dispensable for MAS pathogenesis. Collectively, our data demonstrate that ILC1s undergo apoptosis during TLR-triggering and are dispensable for MAS pathogenesis.

7.
Gen Comp Endocrinol ; 320: 114011, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35231488

RESUMO

Vasoinhibin is a pleiotropic protein hormone with endocrine, autocrine, and paracrine effects on blood vessel growth, permeability, and dilation, and a role in several human diseases. It is generated by proteolytic cleavage of the pituitary hormone prolactin by cathepsin D. Several isoforms with a variation in the number of amino acids and corresponding molecular mass exist. This in silico study investigated the cathepsin D cleavage sites in prolactin responsible for the generation of vasoinhibin in vertebrate species. Ninety-one prolactin protein sequences from species of the taxa primates, rodents, laurasiatheria, mammals, sauropsida, and fish were retrieved, and a multiple sequence alignment was performed. Each sequence was investigated for the presence of a vasoinhibin-generating cathepsin D cleavage site and its corresponding substrate affinity using a scoring system. Primates demonstrated the highest substrate affinity for the generation of the 15 kDa vasoinhibin isoform, and fish the highest affinity for the 16.8 kDa isoform. In both cases, this associates to the presence of leucine in the cleavage site, which is not present in species of the other taxa. In primate evolution, the presence of leucine in the cleavage site occurs with the emergence of simiiformes 42 million years ago and is conserved in higher primates across all subsequent speciation nodes. The 17.2 kDa vasoinhibin isoform has a constant substrate affinity in all taxa. The presence of leucine in vasoinhibin generating cleavage sites appears as an important feature of the molecular evolution of vasoinhibin.


Assuntos
Prolactina , Vertebrados , Sequência de Aminoácidos , Animais , Mamíferos/metabolismo , Filogenia , Prolactina/metabolismo , Proteólise , Vertebrados/genética , Vertebrados/metabolismo
8.
Eur J Immunol ; 49(5): 747-757, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30802297

RESUMO

Infection with Clostridium difficile is one of the major causes of health care acquired diarrhea and colitis. Signaling though MyD88 downstream of TLRs is critical for initiating the early protective host response in mouse models of C. difficile infection (CDI). In the intestine, MyD88 is expressed in various tissues and cell types, such as the intestinal epithelium and mononuclear phagocytes (MNP), including DC or macrophages. Using a genetic gain-of-function system, we demonstrate here that restricting functional MyD88 signaling to the intestinal epithelium, but also to MNPs is sufficient to protect mice during acute CDI by upregulation of the intestinal barrier function and recruitment of neutrophils. Nevertheless, we also show that mice depleted for CD11c-expressing MNPs in the intestine display no major defects in mounting an effective inflammatory response, indicating that the absence of these cells is irrelevant for inducing host protection during acute infection. Together, our results highlight the importance of epithelial-specific MyD88 signaling and demonstrate that although functional MyD88 signaling in DC and macrophages alone is sufficient to correct the phenotype of MyD88-deficiency, these cells do not seem to be essential for host protection in MyD88-sufficient animals during acute infection with C. difficile.


Assuntos
Clostridioides difficile/imunologia , Enterocolite Pseudomembranosa/imunologia , Enterocolite Pseudomembranosa/metabolismo , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Enterocolite Pseudomembranosa/microbiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Mucosa Intestinal/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos
9.
PLoS Pathog ; 13(5): e1006357, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28520792

RESUMO

MyD88-mediated signaling downstream of Toll-like receptors and the IL-1 receptor family is critically involved in the induction of protective host responses upon infections. Although it is known that MyD88-deficient mice are highly susceptible to a wide range of bacterial infections, the cell type-specific contribution of MyD88 in protecting the host against intestinal bacterial infection is only poorly understood. In order to investigate the importance of MyD88 in specific immune and nonimmune cell types during intestinal infection, we employed a novel murine knock-in model for MyD88 that enables the cell type-specific reactivation of functional MyD88 expression in otherwise MyD88-deficient mice. We report here that functional MyD88 signaling in CD11c+ cells was sufficient to activate intestinal dendritic cells (DC) and to induce the early group 3 innate lymphoid cell (ILC3) response as well as the development of colonic Th17/Th1 cells in response to infection with the intestinal pathogen C. rodentium. In contrast, restricting MyD88 signaling to several other cell types, including macrophages (MO), T cells or ILC3 did not induce efficient intestinal immune responses upon infection. However, we observed that the functional expression of MyD88 in intestinal epithelial cells (IEC) also partially protected the mice during intestinal infection, which was associated with enhanced epithelial barrier integrity and increased expression of the antimicrobial peptide RegIIIγ and the acute phase protein SAA1 by epithelial cells. Together, our data suggest that MyD88 signaling in DC and IEC is both essential and sufficient to induce a full spectrum of host responses upon intestinal infection with C. rodentium.


Assuntos
Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Animais , Colo/imunologia , Colo/microbiologia , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/patologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Técnicas de Introdução de Genes , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/metabolismo , Células Th1/imunologia , Células Th1/microbiologia , Células Th17/imunologia , Células Th17/microbiologia , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
10.
Infect Immun ; 82(3): 1052-63, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24343652

RESUMO

Allergies are mainly characterized as an unrestrained Th2-biased immune response. Epidemiological data associate protection from allergic diseases with the exposure to certain infectious agents during early stages of life. Modulation of the immune response by pathogens has been considered to be a major factor influencing this protection. Recent evidence indicates that immunoregulatory mechanisms induced upon infection ameliorate allergic disorders. A longitudinal study has demonstrated reduced frequency and incidence of asthma in children who reported a prior infection with Salmonella. Experimental studies involving Salmonella enterica serovar Typhimurium-infected murine models have confirmed protection from induced allergic airway inflammation; however, the underlying cause leading to this amelioration remains incompletely defined. In this study, we aimed to delineate the regulatory function of Salmonella Typhimurium infection in the amelioration of allergic airway inflammation in mice. We observed a significant increase in CD11b+ Gr1+ myeloid cell populations in mice after infection with S. Typhimurium. Using in vitro and in vivo studies, we confirmed that these myeloid cells reduce airway inflammation by influencing Th2 cells. Further characterization showed that the CD11b+ Gr1+ myeloid cells exhibited their inhibitory effect by altering GATA-3 expression and interleukin-4 (IL-4) production by Th2 cells. These results indicate that the expansion of myeloid cells upon S. Typhimurium infection could potentially play a significant role in curtailing allergic airway inflammation. These findings signify the contribution of myeloid cells in preventing Th2-mediated diseases and suggest their possible application as therapeutics.


Assuntos
Antígeno CD11b/imunologia , Hipersensibilidade/imunologia , Inflamação/imunologia , Receptores de Quimiocinas/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Animais , Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/imunologia , Fator de Transcrição GATA3/imunologia , Hipersensibilidade/microbiologia , Inflamação/microbiologia , Interleucina-4/imunologia , Estudos Longitudinais , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/imunologia , Células Mieloides/microbiologia , Infecções por Salmonella/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Células Th2/imunologia , Células Th2/microbiologia
11.
Sci Immunol ; 7(75): eabo6641, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-36054340

RESUMO

Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of murine group 1 ILCs. Whereas cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s, persist until adulthood, and undergo a specific developmental program. Whereas embryonically derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes the full spectrum of ILC1s. Our findings uncover key ontogenic features of murine group 1 ILCs and their association with cellular identities and functions.


Assuntos
Imunidade Inata , Células Matadoras Naturais , Animais , Feto , Fígado , Camundongos
12.
Sci Immunol ; 7(68): eabi6112, 2022 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-35213210

RESUMO

Group 1 innate lymphoid cells (ILCs), which comprise both natural killer (NK) cells and ILC1s, are important innate effectors that can also positively and negatively influence adaptive immune responses. The latter function is generally ascribed to the ability of NK cells to recognize and kill activated T cells. Here, we used multiphoton intravital microscopy in mouse models of hepatitis B to study the intrahepatic behavior of group 1 ILCs and their cross-talk with hepatitis B virus (HBV)-specific CD8+ T cells. We found that hepatocellular antigen recognition by effector CD8+ T cells triggered a prominent increase in the number of hepatic NK cells and ILC1s. Group 1 ILCs colocalized and engaged in prolonged interactions with effector CD8+ T cells undergoing hepatocellular antigen recognition; however, they did not induce T cell apoptosis. Rather, group 1 ILCs constrained CD8+ T cell proliferation by controlling local interleukin-2 (IL-2) availability. Accordingly, group 1 ILC depletion, or genetic removal of their IL-2 receptor a chain, considerably increased the number of intrahepatic HBV-specific effector CD8+ T cells and the attendant immunopathology. Together, these results reveal a role for group 1 ILCs in controlling T cell-mediated liver immunopathology by limiting local IL-2 concentration and have implications for the treatment of chronic HBV infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade Inata/imunologia , Interleucina-2/imunologia , Linfócitos/imunologia , Animais , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
13.
Mol Cell Endocrinol ; 538: 111471, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34601001

RESUMO

Vasoinhibin is an antiangiogenic, profibrinolytic peptide generated by the proteolytic cleavage of the pituitary hormone prolactin by cathepsin D, matrix metalloproteinases, and bone morphogenetic protein-1. Vasoinhibin can also be generated when placental lactogen or growth hormone are enzymatically cleaved. Here, it is investigated whether plasmin cleaves human prolactin and placental lactogen to generate vasoinhibin-like peptides. Co-incubation of prolactin and placental lactogen with plasmin was performed and analyzed by gel electrophoresis and Western blotting. Mass spectrometric analyses were carried out for sequence validation and precise cleavage site identification. The cleavage sites responsible for the generation of the vasoinhibin-like peptides were located at K170-E171 in prolactin and R160-T161 in placental lactogen. Various genetic variants of the human prolactin and placental lactogen genes are projected to affect proteolytic generation of the vasoinhibin-like peptides. The endogenous counterparts of the vasoinhibin-like peptides generated by plasmin may represent vasoinhibin-isoforms with inhibitory effects on vasculature and coagulation.


Assuntos
Fibrinolisina/metabolismo , Peptídeos/análise , Lactogênio Placentário/química , Prolactina/química , Proteínas de Ciclo Celular/química , Variação Genética , Células HEK293 , Humanos , Espectrometria de Massas , Lactogênio Placentário/genética , Prolactina/genética , Proteólise
14.
J Interferon Cytokine Res ; 40(6): 292-300, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32364818

RESUMO

Interferon-λ (IFN-λ) plays an important role in mucosal immunity, but reliable information regarding the expression of the IFN-λ receptor in individual cells is still missing. One reason for this knowledge gap is the lack of antibodies that specifically recognize the unique IFNLR1 subunit of the dimeric IFN-λ receptor complex. In this study, we investigated whether a reporter mouse carrying a bacterial ß-galactosidase gene inserted into the Ifnlr1 locus could be used to visualize IFN-λ receptor-expressing cells in whole organs. First we confirmed that insertion of the reporter cassette inactivated the Ifnlr1 gene, and that gene function could be restored by removing the ß-galactosidase insert by site-specific recombination. When whole tissues were analyzed, prominent ß-galactosidase activity was confined to the intestinal tract of reporter mice. However, only the snout expressed ß-galactosidase at levels high enough for reliable detection in whole tissue extracts. Interestingly, individual epithelial cells in the upper airways expressed ß-galactosidase activity to variable degrees as determined by flow cytometry and histology, suggesting a remarkable heterogeneity in IFNLR1 expression levels. Taken together, our results demonstrate a surprisingly strong within- and cross-tissue heterogeneity of IFNLR1 expression that may have physiological implications.


Assuntos
Receptores de Interferon/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptor de Interferon gama
15.
Sci Rep ; 10(1): 3404, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32099040

RESUMO

Concerted evolution is often observed in multigene families such as the CEA gene family. As a result, sequence similarity of paralogous genes is significantly higher than expected from their evolutionary distance. Gene conversion, a "copy paste" DNA repair mechanism that transfers sequences from one gene to another and homologous recombination are drivers of concerted evolution. Nevertheless, some gene family members escape concerted evolution and acquire sufficient sequence differences that orthologous genes can be assigned in descendant species. Reasons why some gene family members can escape while others are captured by concerted evolution are poorly understood. By analyzing the entire CEA gene family in cattle (Bos taurus) we identified a member (CEACAM32) that was created by gene duplication and cooption of a unique transmembrane domain exon in the most recent ancestor of ruminants. CEACAM32 shows a unique, testis-specific expression pattern. Phylogenetic analysis indicated that CEACAM32 is not involved in concerted evolution of CEACAM1 paralogs in ruminants. However, analysis of gene conversion events revealed that CEACAM32 is subject to gene conversion but remarkably, these events are found in the leader exon and intron sequences but not in exons coding for the Ig-like domains. These findings suggest that natural selection hinders gene conversion affecting protein sequences of the mature protein and thereby support escape of CEACAM32 from concerted evolution.


Assuntos
Antígenos CD/genética , Bovinos/genética , Moléculas de Adesão Celular/genética , Evolução Molecular , Seleção Genética , Animais , Éxons , Íntrons , Domínios Proteicos
16.
Cell Rep ; 33(11): 108498, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33326784

RESUMO

Natural killer (NK) cells are innate lymphocytes with the capacity to elicit adaptive features, including clonal expansion and immunological memory. Because signal transducer and activator of transcription 5 (STAT5) is essential for NK cell development, the roles of this transcription factor and its upstream cytokines interleukin-2 (IL-2) and IL-15 during infection have not been carefully investigated. In this study, we investigate how STAT5 regulates transcription during viral infection. We demonstrate that STAT5 is induced in NK cells by IL-12 and STAT4 early after infection and that partial STAT5 deficiency results in a defective capacity of NK cells to generate long-lived memory cells. Furthermore, we find a functional dichotomy of IL-2 and IL-15 signaling outputs during viral infection, whereby both cytokines drive clonal expansion, but only IL-15 is required for memory NK cell survival. We thus highlight a role for STAT5 signaling in promoting an optimal anti-viral NK cell response.


Assuntos
Células Matadoras Naturais/metabolismo , Fator de Transcrição STAT5/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais
17.
Artigo em Inglês | MEDLINE | ID: mdl-29163363

RESUMO

BACKGROUND: A dysregulation of the generation of vasoinhibin hormones by proteolytic cleavage of prolactin (PRL) has been brought into context with diabetic retinopathy, retinopathy of prematurity, preeclampsia, pregnancy-induced hypertension, and peripartum cardiomyopathy. Factors governing vasoinhibin generation are incompletely characterized, and the composition of vasoinhibin isoforms in human tissues or compartments, such as the circulation, is unknown. The aim of this study was to determine the possible contribution of PRL point mutations to the generation of vasoinhibins as well as to project their role in vasoinhibin-related diseases. METHODS: Prolactin sequences, point mutations, and substrate specificity information about the PRL cleaving enzymes cathepsin D, matrix metalloproteinases 8 and 13, and bone-morphogenetic protein 1 were retrieved from public databases. The consequences of point mutations in regard to their possible effect on vasoinhibin levels were projected on the basis of a score indicating the suitability of a particular sequence for enzymatic cleavage that result in vasoinhibin generation. The relative abundance and type of vasoinhibin isoforms were estimated by comparing the relative cleavage efficiency of vasoinhibin-generating enzymes. RESULTS: Six point mutations leading to amino acid substitutions in vasoinhibin-generating cleavage sites were found and projected to either facilitate or inhibit vasoinhibin generation. Four mutations affecting vasoinhibin generation in cancer tissues were found. The most likely composition of the relative abundance of vasoinhibin isoforms is projected to be 15 > 17.2 > 16.8 > 17.7 > 18 kDa vasoinhibin. CONCLUSION: Prolactin point mutations are likely to influence vasoinhibin levels by affecting the proteolysis efficiency of vasoinhibin-generating enzymes and should be monitored in patients with vasoinhibin-related diseases. Attempts to characterize vasoinhibin-related diseases should include the 15, 17.2, 16.8, 17.7, and 18 kDa vasoinhibin isoforms.

18.
Nat Med ; 20(11): 1327-33, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25282359

RESUMO

Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (TH17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse TH17 cells and promotes the development of anti-inflammatory Foxp3(+) regulatory T (Treg) cells. We show that TH17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although TH17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates TH17 cell-mediated autoimmune disease. Our results indicate fundamental differences between TH17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of TH17 cell-mediated inflammatory diseases.


Assuntos
Linhagem da Célula , Ácidos Graxos/biossíntese , Linfócitos T Reguladores/citologia , Células Th17/citologia , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Humanos , Imunização , Lipogênese/efeitos dos fármacos , Macrolídeos/química , Macrolídeos/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
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