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1.
Cell Immunol ; 401-402: 104842, 2024.
Article de Anglais | MEDLINE | ID: mdl-38897020

RÉSUMÉ

Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.


Sujet(s)
Antigènes CD , Intégrines alpha , Sous-famille B des récepteurs de cellules NK de type lectine , Polypes du nez , Rhinite , Sinusite , Humains , Polypes du nez/immunologie , Sinusite/immunologie , Intégrines alpha/métabolisme , Intégrines alpha/immunologie , Antigènes CD/métabolisme , Antigènes CD/immunologie , Maladie chronique , Rhinite/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/métabolisme , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Femelle , Mâle , Adulte d'âge moyen , Adulte , Muqueuse nasale/immunologie , Lymphocytes T/immunologie , Lymphocytes T/métabolisme , Antigènes de différenciation des lymphocytes T/métabolisme , Antigènes de différenciation des lymphocytes T/immunologie , Interleukine-17/métabolisme , Interleukine-17/immunologie , Antigène CTLA-4/métabolisme , Antigène CTLA-4/immunologie , Interféron gamma/métabolisme , Interféron gamma/immunologie , , Lectines de type C
2.
Int Immunopharmacol ; 133: 112072, 2024 May 30.
Article de Anglais | MEDLINE | ID: mdl-38636371

RÉSUMÉ

OBJECTIVE: This study aimed to investigate the role of KLRB1 (CD161) in human CD4+ T cells and elucidate its significance in primary Sjögren's syndrome (pSS). METHODS: Peripheral blood samples from 37 healthy controls and 44 pSS patients were collected. The publicly available single-cell RNA-Seq data from pSS patient PBMCs were utilized to analyse KLRB1 expression in T cells. KLRB1-expressing T lymphocyte subset proportions in pSS patients and healthy controls were determined by flow cytometry. CD25, Ki-67, cytokine secretion, and chemokine receptor expression in CD4+ KLRB1+ T cells were detected and compared with those in CD4+ KLRB1- T cells. Correlation analysis was conducted between KLRB1-related T-cell subsets and clinical indicators. ROC curves were generated to explore the diagnostic potential of KLRB1 for pSS. RESULTS: KLRB1 was significantly upregulated following T-cell activation, and Ki-67 and CD25 expression was significantly greater in CD4+ KLRB1+ T cells than in CD4+ KLRB1- T cells. KLRB1+ CD4+ T cells exhibited greater IL-17A, IL-21, IL-22, and IFN-γ secretion upon stimulation, and there were significantly greater proportions of CCR5+, CCR2+, CX3CR1+, CCR6+, and CXCR3+ cells among CD4+ KLRB1+ T cells than among CD4+ KLRB1- T cells. Compared with that in HCs, KLRB1 expression in CD4+ T cells was markedly elevated in pSS patients and significantly correlated with clinical disease indicators. CONCLUSION: KLRB1 is a characteristic molecule of the CD4+ T-cell activation phenotype. The increased expression of KLRB1 in the CD4+ T cells of pSS patients suggests its potential involvement in the pathogenesis of pSS and its utility as an auxiliary diagnostic marker for pSS.


Sujet(s)
Lymphocytes T CD4+ , Sous-famille B des récepteurs de cellules NK de type lectine , Syndrome de Gougerot-Sjögren , Régulation positive , Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Lymphocytes T CD4+/immunologie , Cytokines/immunologie , Antigène KI-67/métabolisme , Activation des lymphocytes , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Phénotype , Syndrome de Gougerot-Sjögren/diagnostic , Syndrome de Gougerot-Sjögren/génétique , Syndrome de Gougerot-Sjögren/immunologie
3.
Cell Mol Gastroenterol Hepatol ; 15(5): 1181-1198, 2023.
Article de Anglais | MEDLINE | ID: mdl-36787843

RÉSUMÉ

BACKGROUND & AIMS: CD161-expressing CD8+ T cells consist of mucosal-associated invariant T cells with semi-invariant T-cell receptor (TCR) use and non-mucosal-associated invariant T CD161+CD8+ T cells with polyclonal TCR repertoire. Although CD161+CD8+ T cells are enriched in liver and embrace hepatitis B virus (HBV)-specific T cells in chronic hepatitis B (CHB) patients, their roles in disease progression remain poorly understood. This study aimed to decipher their profiling and dynamic changes during chronic HBV infection. METHODS: Blood samples from 257 CHB patients and nontumor liver specimens from 73 HBV-positive patients were analyzed for CD161+CD8+ T-cell characterization by flow cytometry, TCR repertoire determination, transcriptomic analyses, and cell experiments. RESULTS: CD161+CD8+ T cells were increased and hyperactivated in patients, while positive correlation between the CD161+CD8+ T-cell ratio and HBV-DNA level suggested this was insufficient to control HBV replication. The overlap of complementarity determining region 3 sequences supported the switch between CD161-CD8+ and CD161+CD8+ populations. Although CD161+CD8+ T cells were endowed with innateness phenotype and enhanced antiviral capacity, the population from patients had impaired type I cytokine production, and increased interleukin 17 and granzyme B secretion. The increased CD161+CD8+ T cells and their increased granzyme B secretion correlated positively with inflammation-associated liver injury. Hepatic CD161+CD8+ T cells showed neutrophil-related pathogenic potential because they had increased transcript signatures and proinflammatory cytokine production in neutrophil recruitment- and response-related pathways that changed consistently in the injured liver. CONCLUSIONS: Our results highlight the reduced antiviral potency but increased pathogenic potential of CD161+CD8+ T cells in CHB patients, supporting CD161 expression as a marker of pathogenic CD8+ T subset and the intervention target for liver injury.


Sujet(s)
Lymphocytes T CD8+ , Hépatite B chronique , Humains , Antiviraux , Granzymes , Virus de l'hépatite B , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie
4.
Nat Commun ; 13(1): 3357, 2022 06 10.
Article de Anglais | MEDLINE | ID: mdl-35688805

RÉSUMÉ

Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n = 21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log10 cells per swab respectively (p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decrease post-vaccination. Similar increases in nasal CD8+CD69+CD103- T cells are observed, particularly following the second dose. CD4+ cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8+ T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months (p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.


Sujet(s)
Lymphocytes T CD8+ , COVID-19 , Vaccin BNT162 , Lymphocytes T CD4+ , COVID-19/prévention et contrôle , Vaccins contre la COVID-19 , Humains , Mémoire immunologique , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Muqueuse nasale , ARN messager , Récepteurs CCR6 , SARS-CoV-2 , Vaccination
5.
Cancer Sci ; 113(2): 756-769, 2022 Feb.
Article de Anglais | MEDLINE | ID: mdl-34881489

RÉSUMÉ

BACKGROUND: Glioblastoma is a paradigm of cancer-associated immunosuppression, limiting the effects of immunotherapeutic strategies. Thus, identifying the molecular mechanisms underlying immune surveillance evasion is critical. Recently, the preferential expression of inhibitory natural killer (NK) cell receptor CD161 on glioma-infiltrating cytotoxic T cells was identified. Focusing on the molecularly annotated, large-scale clinical samples from different ethnic origins, the data presented here provide evidence of this immune modulator's essential roles in brain tumor biology. METHODS: Retrospective RNA-seq data analysis was conducted in a cohort of 313 patients with glioma in the Chinese Glioma Genome Atlas (CGGA) database and 603 patients in The Cancer Genome Atlas (TCGA) database. In addition, single-cell sequencing data from seven surgical specimens of glioblastoma patients and a model in which patient-derived glioma stem cells were cocultured with peripheral lymphocytes, were used to analyze the molecular evolution process during gliomagenesis. RESULTS: CD161 was enriched in high-grade gliomas and isocitrate dehydrogenase (IDH)-wildtype glioma. CD161 acted as a potential biomarker for the mesenchymal subtype of glioma and an independent prognostic factor for the overall survival (OS) of patients with glioma. In addition, CD161 played an essential role in inhibiting the cytotoxicity of T cells in glioma patients. During the process of gliomagenesis, the expression of CD161 on different lymphocytes dynamically evolved. CONCLUSION: The expression of CD161 was closely related to the pathology and molecular pathology of glioma. Meanwhile, CD161 promoted the progression and evolution of gliomas through its unique effect on T cell dysfunction. Thus, CD161 is a promising novel target for immunotherapeutic strategies in glioma treatment.


Sujet(s)
Gliome/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Marqueurs biologiques tumoraux/génétique , Bases de données génétiques , Évolution de la maladie , Gliome/génétique , Gliome/mortalité , Gliome/anatomopathologie , Humains , Inhibiteurs de points de contrôle immunitaires/immunologie , Inflammation , Isocitrate dehydrogenases/génétique , Lymphocytes TIL/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Pronostic , Récepteurs aux antigènes des cellules T/immunologie , Lymphocytes T cytotoxiques/immunologie , Transcriptome , Échappement de la tumeur à la surveillance immunitaire
6.
Eur J Immunol ; 51(10): 2531-2534, 2021 10.
Article de Anglais | MEDLINE | ID: mdl-34453339

RÉSUMÉ

Simultaneous triggering of NK1.1 and MHC class I on NK cells gives a higher Ca2+ flux response compared to triggering the NK1.1 receptor alone. The data suggest a novel costimulatory role for MHC class I molecules on NK cell responses.


Sujet(s)
Antigènes Ly/immunologie , Calcium/métabolisme , Antigènes d'histocompatibilité de classe I/immunologie , Cellules tueuses naturelles/immunologie , Cellules tueuses naturelles/métabolisme , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Transduction du signal , Animaux , Antigènes H-2/génétique , Antigènes H-2/immunologie , Souris
7.
Cancer Immunol Immunother ; 70(12): 3617-3627, 2021 Dec.
Article de Anglais | MEDLINE | ID: mdl-33944981

RÉSUMÉ

Echinococcus granulosus is a cestode parasite which causes cystic echinococcosis disease. Previously we observed that vaccination with E. granulosus antigens from human hydatid cyst fluid (HCF) significantly inhibits colon cancer growth. In the present work, we evaluate the anti-tumor immune response induced by human HCF against LL/2 lung cancer in mice. HCF vaccination protected from tumor growth, both in prophylactic and therapeutic settings, and significantly increased mouse survival compared to control mice. Considering that tumor-associated carbohydrate antigens are expressed in E. granulosus, we oxidized terminal carbohydrates in HCF with sodium periodate. This treatment abrogates the anti-tumor activity induced by HCF vaccination. We found that HCF vaccination-induced IgG antibodies that recognize LL/2 tumor cells by flow cytometry. An antigen-specific immune response is induced with HCF vaccination in the tumor-draining lymph nodes and spleen characterized by the production of IL-5 and, in less extent, IFNÉ£. In the tumor microenvironment, we found that NK1.1 positive cells from HCF-treated mice showed higher expression of CD69 than control mice ones, indicating a higher level of activation. When we depleted these cells by administrating the NK-specific antibody NK1.1, a significantly decreased survival was observed in HCF-induced mice, suggesting that NK1.1+ cells mediate the anti-tumor protection induced by HCF. These results suggest that HCF can evoke an integrated anti-tumor immune response involving both, the innate and adaptive components, and provide novel insights into the understanding of the intricate relationship between HCF vaccination and tumor growth.


Sujet(s)
Antigènes Ly/immunologie , Échinococcose/immunologie , Echinococcus granulosus/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Animaux , Lignée cellulaire tumorale , Tumeurs du côlon/immunologie , Humains , Immunité/immunologie , Mâle , Souris , Souris de lignée C57BL , Rate/immunologie , Microenvironnement tumoral/immunologie
8.
JCI Insight ; 6(11)2021 06 08.
Article de Anglais | MEDLINE | ID: mdl-33974561

RÉSUMÉ

NK cells are innate immune cells implicated in ALS; whether NK cells impact ALS in a sex- and age-specific manner was investigated. Herein, NK cells were depleted in male and female SOD1G93A ALS mice, survival and neuroinflammation were assessed, and data were stratified by sex. NK cell depletion extended survival in female but not male ALS mice with sex-specific effects on spinal cord microglia. In humans, NK cell numbers, NK cell subpopulations, and NK cell surface markers were examined in prospectively blood collected from subjects with ALS and control subjects; longitudinal changes in these metrics were correlated to revised ALS functional rating scale (ALSFRS-R) slope and stratified by sex and age. Expression of NK cell trafficking and cytotoxicity markers was elevated in subjects with ALS, and changes in CXCR3+ NK cells and 7 trafficking and cytotoxicity markers (CD11a, CD11b, CD38, CX3CR1, NKG2D, NKp30, NKp46) correlated with disease progression. Age affected the associations between ALSFRS-R and markers NKG2D and NKp46, whereas sex impacted the NKp30 association. Collectively, these findings suggest that NK cells contribute to ALS progression in a sex- and age-specific manner and demonstrate that age and sex are critical variables when designing and assessing ALS immunotherapy.


Sujet(s)
Sclérose latérale amyotrophique/immunologie , Cellules tueuses naturelles/immunologie , Maladies neuro-inflammatoires/immunologie , Moelle spinale/immunologie , Facteurs âges , Sujet âgé , Sclérose latérale amyotrophique/génétique , Sclérose latérale amyotrophique/métabolisme , Animaux , Antigènes Ly/immunologie , Antigènes Ly/métabolisme , Lymphocytes T CD4+/cytologie , Lymphocytes T CD4+/immunologie , Lymphocytes T CD8+/cytologie , Lymphocytes T CD8+/immunologie , Granulocytes éosinophiles/cytologie , Granulocytes éosinophiles/immunologie , Femelle , Humains , Cellules tueuses naturelles/cytologie , Cellules tueuses naturelles/métabolisme , Leucocytes/cytologie , Leucocytes/immunologie , Mâle , Souris , Souris transgéniques , Adulte d'âge moyen , Monocytes/cytologie , Monocytes/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/métabolisme , Granulocytes neutrophiles/cytologie , Granulocytes neutrophiles/immunologie , Facteurs sexuels , Moelle spinale/cytologie , Superoxide dismutase/génétique , Taux de survie
9.
Immunity ; 54(6): 1320-1337.e4, 2021 06 08.
Article de Anglais | MEDLINE | ID: mdl-33945787

RÉSUMÉ

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s) are heterogenous innate lymphocytes broadly defined in mice as Lin-NK1.1+NKp46+ cells that express the transcription factor T-BET and produce interferon-γ. The ILC1 definition primarily stems from studies on liver and small intestinal populations. However, NK1.1+NKp46+ cells in the salivary glands, uterus, adipose, and other tissues exhibit nonuniform programs that differ from those of liver or intestinal ILC1s or NK cells. Here, we performed single-cell RNA sequencing on murine NK1.1+NKp46+ cells from blood, spleen, various tissues, and solid tumors. We identified gene expression programs of tissue-specific ILC1s, tissue-specific NK cells, and non-tissue-specific populations in blood, spleen, and other tissues largely corresponding to circulating cells. Moreover, we found that circulating NK cell programs were reshaped in tumor-bearing mice. Core programs of circulating and tumor NK cells paralleled conserved human NK cells signatures, advancing our understanding of the human NK-ILC1 spectrum.


Sujet(s)
Immunité innée/immunologie , Cellules tueuses naturelles/immunologie , Lymphocytes/immunologie , Animaux , Lignée cellulaire tumorale , Femelle , Humains , Mâle , Souris , Souris de lignée C57BL , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Récepteur-1 de déclenchement de cytotoxicité naturelle/immunologie , Tumeurs/immunologie , Analyse sur cellule unique/méthodes , Facteurs de transcription/immunologie
10.
Microbiol Immunol ; 64(7): 532-539, 2020 Jul.
Article de Anglais | MEDLINE | ID: mdl-32343447

RÉSUMÉ

Immunologic abnormalities of natural killer (NK) cells and T cells play a role in the pathogenesis of systemic lupus erythematosus (SLE). CD161 is expressed on most of the NK cells and on some T cells. The quantities of CD161-expressing cells and expression levels of CD161 were analyzed in T cells and NK cells from patients with SLE compared with normal controls. The expression of CD161 on NK cells, NKT cells, CD4+ T cells, and CD8+ T cells in peripheral blood from patients with inactive SLE and active SLE, and from the normal controls group were determined using flow cytometry. The frequency and expression level of CD161 in the lymphocyte subsets and its relationship with the quantity of regulatory T cells, anti-double stranded DNA antibody, and the titer of antinuclear antibody were evaluated. Both the percentages of the CD161+ subpopulation and the mean fluorescence intensities (MFIs) of CD161 in CD8+ T cells and NKT cells decreased significantly in SLE patients compared with normal controls (P < .001). The CD161 expression in CD8+ T cells and NKT cells also decreased in the anti-dsDNA (+) group (P < .05). The counts of Treg cells were lower in SLE patients and were weakly correlated with the percentage of the CD161 subpopulation (r = 0.229, P = .016) and the MFIs of CD161 expression in CD8+ T cells (r = .232, P = .014). The frequencies and levels of CD161 expression on CD8+ T cells and NKT cells were reduced in SLE patients, suggesting that an abnormality of these cells was related to the pathogenesis of SLE.


Sujet(s)
Lymphocytes T CD8+/métabolisme , Cellules tueuses naturelles/métabolisme , Lupus érythémateux disséminé/métabolisme , Sous-famille B des récepteurs de cellules NK de type lectine/métabolisme , Cellules T tueuses naturelles/métabolisme , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Lymphocytes T CD8+/immunologie , Femelle , Cytométrie en flux , Humains , Cellules tueuses naturelles/immunologie , Lupus érythémateux disséminé/sang , Lupus érythémateux disséminé/immunologie , Sous-populations de lymphocytes , Mâle , Adulte d'âge moyen , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Cellules T tueuses naturelles/immunologie , Jeune adulte
11.
Mol Immunol ; 120: 136-145, 2020 04.
Article de Anglais | MEDLINE | ID: mdl-32120181

RÉSUMÉ

Evasion of the immune system is often associated with malignant tumors. The cancer cell microenvironment plays an important role in tumor progression, but its mechanism is largely unknown. Here we show that an extracellular compound derived from gastric cancer (GC-EC) selectively suppresses CD161+CD3- natural killer (NK) cells. Splenocytes treated with GC-EC showed considerable proliferation and the CD161+CD3- NK cell population was time-dependently suppressed. Intracellular staining of IFN-γ was shown to be down-regulated in concert with granzyme B and perforin. A cytotoxicity assay of splenocytes treated with GC-EC against K-562 cells showed a significant reduction in cytolytic activity. Further, the immune-suppressive effect of GC-EC was more evident in a syngeneic tumor model in C57BL/6 mice. Animals treated with B16 F10 and GC-EC exhibited more aggravated tumor formation than animals treated with B16 F10 only. We demonstrated that inhibition of apoptosis while increasing PI3 K/AKT levels may provoke tumor formation by GC-EC. A cytokine array revealed the presence of several cytokines in GC-EC that negatively regulate immune cytolytic activity and could be potential candidates for immune-suppressive effects.


Sujet(s)
Cellules tueuses naturelles/immunologie , Tumeurs de l'estomac/immunologie , Animaux , Apoptose/immunologie , Antigènes CD3/immunologie , Prolifération cellulaire , Cytokines/immunologie , Cytotoxicité immunologique , Espace extracellulaire/immunologie , Humains , Tolérance immunitaire , Cellules K562 , Mâle , Mélanome expérimental/immunologie , Mélanome expérimental/métabolisme , Mélanome expérimental/anatomopathologie , Souris , Souris de lignée C57BL , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Rats , Rat Sprague-Dawley , Tumeurs de l'estomac/métabolisme , Tumeurs de l'estomac/anatomopathologie , Microenvironnement tumoral/immunologie
12.
J Virol ; 94(1)2019 12 12.
Article de Anglais | MEDLINE | ID: mdl-31597762

RÉSUMÉ

Natural killer (NK) cells are a subset of innate lymphoid cells (ILC) capable of recognizing stressed and infected cells through multiple germ line-encoded receptor-ligand interactions. Missing-self recognition involves NK cell sensing of the loss of host-encoded inhibitory ligands on target cells, including MHC class I (MHC-I) molecules and other MHC-I-independent ligands. Mouse cytomegalovirus (MCMV) infection promotes a rapid host-mediated loss of the inhibitory NKR-P1B ligand Clr-b (encoded by Clec2d) on infected cells. Here we provide evidence that an MCMV m145 family member, m153, functions to stabilize cell surface Clr-b during MCMV infection. Ectopic expression of m153 in fibroblasts augments Clr-b cell surface levels. Moreover, infections using m153-deficient MCMV mutants (Δm144-m158 and Δm153) show an accelerated and exacerbated Clr-b downregulation. Importantly, enhanced loss of Clr-b during Δm153 mutant infection reverts to wild-type levels upon exogenous m153 complementation in fibroblasts. While the effects of m153 on Clr-b levels are independent of Clec2d transcription, imaging experiments revealed that the m153 and Clr-b proteins only minimally colocalize within the same subcellular compartments, and tagged versions of the proteins were refractory to coimmunoprecipitation under mild-detergent conditions. Surprisingly, the Δm153 mutant possesses enhanced virulence in vivo, independent of both Clr-b and NKR-P1B, suggesting that m153 potentially targets additional host factors. Nevertheless, the present data highlight a unique mechanism by which MCMV modulates NK ligand expression.IMPORTANCE Cytomegaloviruses are betaherpesviruses that in immunocompromised individuals can lead to severe pathologies. These viruses encode various gene products that serve to evade innate immune recognition. NK cells are among the first immune cells that respond to CMV infection and use germ line-encoded NK cell receptors (NKR) to distinguish healthy from virus-infected cells. One such axis that plays a critical role in NK recognition involves the inhibitory NKR-P1B receptor, which engages the host ligand Clr-b, a molecule commonly lost on stressed cells ("missing-self"). In this study, we discovered that mouse CMV utilizes the m153 glycoprotein to circumvent host-mediated Clr-b downregulation, in order to evade NK recognition. These results highlight a novel MCMV-mediated immune evasion strategy.


Sujet(s)
Interactions hôte-pathogène/génétique , Cellules tueuses naturelles/virologie , Lectines de type C/génétique , Muromegalovirus/génétique , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Récepteurs immunologiques/génétique , Protéines de la matrice virale/génétique , Animaux , Régulation de l'expression des gènes/immunologie , Test de complémentation , Infections à Herpesviridae , Interactions hôte-pathogène/immunologie , Immunité innée , Cellules tueuses naturelles/immunologie , Lectines de type C/immunologie , Souris , Souris de lignée C57BL , Souris knockout , Muromegalovirus/immunologie , Muromegalovirus/pathogénicité , Cellules NIH 3T3 , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Récepteurs immunologiques/immunologie , Transduction du signal , Charge virale , Protéines de la matrice virale/déficit , Protéines de la matrice virale/immunologie , Réplication virale
13.
Front Immunol ; 10: 1922, 2019.
Article de Anglais | MEDLINE | ID: mdl-31474991

RÉSUMÉ

Recent evidence suggests that the primary progressive form of multiple sclerosis (PP-MS) may present with specific immunological alterations. In this study we focused our attention on CD161, an NK and T cell marker upregulated in relapsing-remitting MS, and investigated its transcript and protein levels in blood cells from PP-MS and healthy individuals. We demonstrated transcriptional downregulation of CD161 in PP-MS and described concomitant mRNA reduction for RORgt, CCR6, CXCR6, KLRK1/NKG2D and many other markers typical of mucosa associated invariant T (MAIT) cells. Targeted multiparametric flow cytometry on fresh blood cells from an independent cohort of case-control subjects confirmed the selective loss of circulating CD8 CD161high T cells, which consist mainly of MAIT cells, and not of CD8 CD161int T cells in PP-MS. These data demonstrate alterations in a specific circulating immune cell subset in MS patients with progressive onset.


Sujet(s)
Lymphocytes T CD8+/immunologie , Cellules T invariantes associées aux muqueuses/immunologie , Sclérose en plaques chronique progressive/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Adulte , Lymphocytes T CD8+/métabolisme , Études de cohortes , Femelle , Analyse de profil d'expression de gènes/méthodes , Humains , Mâle , Adulte d'âge moyen , Cellules T invariantes associées aux muqueuses/métabolisme , Sclérose en plaques chronique progressive/sang , Sclérose en plaques chronique progressive/génétique , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Sous-famille B des récepteurs de cellules NK de type lectine/métabolisme , Sous-famille K des récepteurs de cellules NK de type lectine/génétique , Sous-famille K des récepteurs de cellules NK de type lectine/immunologie , Sous-famille K des récepteurs de cellules NK de type lectine/métabolisme , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/génétique , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/immunologie , Membre-3 du groupe F de la sous-famille-1 de récepteurs nucléaires/métabolisme , Récepteurs CCR6/génétique , Récepteurs CCR6/immunologie , Récepteurs CCR6/métabolisme , Récepteurs CXCR6/génétique , Récepteurs CXCR6/immunologie , Récepteurs CXCR6/métabolisme
14.
J Immunol ; 203(7): 1981-1988, 2019 10 01.
Article de Anglais | MEDLINE | ID: mdl-31444264

RÉSUMÉ

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


Sujet(s)
Interféron gamma/immunologie , Cellules tueuses naturelles/immunologie , Proteasome endopeptidase complex/immunologie , Biosynthèse des protéines/immunologie , Transduction du signal/immunologie , Transcription génétique/immunologie , Animaux , Antigènes Ly/génétique , Antigènes Ly/immunologie , Interféron gamma/génétique , Cellules tueuses naturelles/cytologie , Souris , Souris knockout , Sous-famille A des récepteurs de cellules NK de type lectine/génétique , Sous-famille A des récepteurs de cellules NK de type lectine/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Récepteur-1 de déclenchement de cytotoxicité naturelle/génétique , Récepteur-1 de déclenchement de cytotoxicité naturelle/immunologie , Proteasome endopeptidase complex/génétique , Transduction du signal/génétique
15.
Am J Physiol Heart Circ Physiol ; 317(3): H517-H530, 2019 09 01.
Article de Anglais | MEDLINE | ID: mdl-31172810

RÉSUMÉ

Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a+/CD68+ M1 macrophages into the renal medulla. Renal inflammation is implicated in renal sodium retention and the development of hypertension. Renal denervation is known to decrease renal inflammation. The objective of this study was to determine the role of CD161a+/CD68+ macrophages and renal sympathetic nerves in cholinergic-hypertension and renal sodium retention. Bilateral renal nerve denervation (RND) and immune ablation of CD161a+ immune cells were performed in young prehypertensive spontaneously hypertensive rat (SHR) followed by infusion of either saline or nicotine (15 mg·kg-1·day-1) for 2 wk. Immune ablation was conducted by injection of unconjugated azide-free antibody targeting rat CD161a+. Blood pressure was monitored by tail cuff plethysmography. Tissues were harvested at the end of infusion. Nicotine induced premature hypertension, renal expression of the sodium-potassium chloride cotransporter (NKCC2), increases in renal sodium retention, and infiltration of CD161a+/CD68+ macrophages into the renal medulla. All of these effects were abrogated by RND and ablation of CD161a+ immune cells. Cholinergic activation of CD161a+ immune cells with nicotine leads to the premature development of hypertension in SHR. The effects of renal sympathetic nerves on chemotaxis of CD161a+ macrophages to the renal medulla, increased renal expression of NKCC2, and renal sodium retention contribute to cholinergic hypertension. The CD161a+ immune cells are necessary and essential for this prohypertensive nicotine-mediated inflammatory response.NEW & NOTEWORTHY This is the first study that describes a novel integrative physiological interaction between the adrenergic, cholinergic, and renal systems in the development of hypertension, describing data for the role of each in a genetic model of essential hypertension. Noteworthy findings include the prevention of nicotine-mediated hypertension following successful immune ablation of CD161a+ immune cells and the necessary role these cells play in the overexpression of the sodium-potassium-chloride cotransporter (NKCC2) in the renal medulla and renal sodium retention. Renal infiltration of these cells is demonstrated to be dependent on the presence of renal adrenergic innervation. These data offer a fertile ground of therapeutic potential for the treatment of hypertension as well as open the door for further investigation into the mechanism involved in inflammation-mediated renal sodium transporter expression. Taken together, these findings suggest immune therapy, renal denervation, and, possibly, other new molecular targets as having a potential role in the development and maintenance of essential hypertension.


Sujet(s)
Anticorps monoclonaux/administration et posologie , Pression sanguine , Hypertension artérielle/prévention et contrôle , Rein , Macrophages/effets des médicaments et des substances chimiques , Sous-famille B des récepteurs de cellules NK de type lectine/antagonistes et inhibiteurs , Nicotine , Agonistes nicotiniques , Phénol/administration et posologie , Artère rénale/innervation , Réabsorption rénale , Sodium/urine , Sympathectomie chimique , Animaux , Modèles animaux de maladie humaine , Hypertension artérielle/induit chimiquement , Hypertension artérielle/immunologie , Hypertension artérielle/physiopathologie , Médiateurs de l'inflammation/immunologie , Rein/vascularisation , Rein/effets des médicaments et des substances chimiques , Rein/immunologie , Macrophages/immunologie , Mâle , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Rats de lignée SHR , Membre-1 de la famille-12 des transporteurs de solutés/métabolisme
16.
Mol Cell Biochem ; 458(1-2): 159-169, 2019 Aug.
Article de Anglais | MEDLINE | ID: mdl-31020492

RÉSUMÉ

Cyclosporin A (CSA) is a widely used drug to prevent the immune cell function. It is well known that CSA blocks transcription of cytokine genes in activated T cells. The connection between T cells and CSA has been well established. However, the effect of CSA on natural killer (NK) cells is not thoroughly understood. Therefore, in the present study, splenocytes and peripheral blood mononuclear cells (PBMCs) were treated with CSA in the presence of concanavalin A (Con A) or interleukin-2 (IL-2). CSA at higher concentrations induces apoptosis and inhibition of proliferation, while lower concentrations showed synergistically enhanced proliferation in splenocytes and PBMCs. Further, CSA favored the in vitro conversion of CD3+CD161+ cells. Splenocytes and PBMC were found to have synergistic proliferation with Con A, and PBMC exhibited significantly higher expression of NKp30, NKp44, and granzyme B along with enhanced cytotoxicity against K-562 cells in CSA-treated animals. Proliferation assay also showed that proliferation of CD161+ cells was higher in CSA-treated animals. Collectively, our results suggest that CSA differentially influences the population, function, and expression of the NK cell phenotype.


Sujet(s)
Antigènes CD3/immunologie , Prolifération cellulaire/effets des médicaments et des substances chimiques , Ciclosporine/pharmacologie , Cellules tueuses naturelles/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Animaux , Apoptose/effets des médicaments et des substances chimiques , Apoptose/immunologie , Concanavaline A/pharmacologie , Relation dose-effet des médicaments , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Régulation de l'expression des gènes/immunologie , Granzymes/immunologie , Humains , Interleukine-2/pharmacologie , Cellules K562 , Cellules tueuses naturelles/cytologie , Mâle , Récepteur-2 de déclenchement de cytotoxicité naturelle/immunologie , Récepteur-3 de déclenchement de cytotoxicité naturelle/immunologie , Rats , Rat Sprague-Dawley
17.
J Virol ; 93(7)2019 04 01.
Article de Anglais | MEDLINE | ID: mdl-30700608

RÉSUMÉ

HIV infection is controlled immunologically in a small subset of infected individuals without antiretroviral therapy (ART), though the mechanism of control is unclear. CD8+ T cells are a critical component of HIV control in many immunological controllers. NK cells are also believed to have a role in controlling HIV infection, though their role is less well characterized. We used mass cytometry to simultaneously measure the levels of expression of 24 surface markers on peripheral NK cells from HIV-infected subjects with various degrees of HIV natural control; we then used machine learning to identify NK cell subpopulations that differentiate HIV controllers from noncontrollers. Using CITRUS (cluster identification, characterization, and regression), we identified 3 NK cell subpopulations that differentiated subjects with chronic HIV viremia (viremic noncontrollers [VNC]) from individuals with undetectable HIV viremia without ART (elite controllers [EC]). In a parallel approach, we identified 11 NK cell subpopulations that differentiated HIV-infected subject groups using k-means clustering after dimensionality reduction by t-neighbor stochastic neighbor embedding (tSNE) or linear discriminant analysis (LDA). Among these additional 11 subpopulations, the frequencies of 5 correlated with HIV DNA levels; importantly, significance was retained in 2 subpopulations in analyses that included only cohorts without detectable viremia. By comparing the surface marker expression patterns of all identified subpopulations, we revealed that the CD11b+ CD57- CD161+ Siglec-7+ subpopulation of CD56dim CD16+ NK cells are more abundant in EC and HIV-negative controls than in VNC and that the frequency of these cells correlated with HIV DNA levels. We hypothesize that this population may have a role in immunological control of HIV infection.IMPORTANCE HIV infection results in the establishment of a stable reservoir of latently infected cells; ART is usually required to keep viral replication under control and disease progression at bay, though a small subset of HIV-infected subjects can control HIV infection without ART through immunological mechanisms. In this study, we sought to identify subpopulations of NK cells that may be involved in the natural immunological control of HIV infection. We used mass cytometry to measure surface marker expression on peripheral NK cells. Using two distinct semisupervised machine learning approaches, we identified a CD11b+ CD57- CD161+ Siglec-7+ subpopulation of CD56dim CD16+ NK cells that differentiates HIV controllers from noncontrollers. These cells can be sorted out for future functional studies to assess their potential role in the immunological control of HIV infection.


Sujet(s)
Infections à VIH/immunologie , Cellules tueuses naturelles/immunologie , Cellules tueuses naturelles/virologie , Antigènes CD11b/immunologie , Antigènes CD56/immunologie , Antigènes CD57/immunologie , Lymphocytes T CD8+/virologie , Lignée cellulaire tumorale , ADN viral/immunologie , Infections à VIH/virologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/immunologie , Humains , Cellules K562 , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Récepteurs du fragment Fc des IgG/immunologie , Virémie/immunologie , Virémie/virologie
18.
Eur Cytokine Netw ; 30(4): 160-167, 2019 Dec 01.
Article de Anglais | MEDLINE | ID: mdl-32096478

RÉSUMÉ

OBJECTIVE: Stage II melanoma patients have high risk for regional and distant metastases and may benefit from novel therapeutic strategies. To clarify the role of NK cells in Stage II melanoma, we characterized the cytotoxic activity of NK cells and the expression of various activating and inhibitory receptors in high-risk cutaneous melanoma patients (Stages IIB and IIC) compared to low-risk patients (Stage IA). MATERIALS AND METHODS: Native and cytokine-treated peripheral blood mononuclear cells were used for functional and phenotypical analyses. RESULTS: Compared to Stage IA-B patients, Stage IIB-C patients showed significantly decreased NK cell activity, as well as decreased expression of the activating NKG2D and CD161 receptors, most likely due to increased serum levels of the immunosuppressive cytokine TGF-ß1 in these patients. Interestingly, treatment of periperal blood mononuclear cells with IFN-α, IL-2, IL-12 or the combination of IL-12 and IL-18 significantly induced NK cell activity for both groups of melanoma patients. However, only low-risk patients had a significant increase in the expression of the NKG2D receptor after in vitro treatment with IFN-α, as well as an significant increase in the expression of CD161 after treatment with IFN-α or IL-12. Although IL-2 induced the expression of NKG2D in both groups of patients, this increase was significantly lower in high-risk melanoma. CONCLUSION: NK cell parameters may be useful as biomarkers of disease progression in localized melanoma patients. Our results further suggest that the use of NK cell-activating cytokines in combination with inhibitors of immunosuppressive factors like TGF-ß1 could be a therapeutic option for the treatment of high-risk cutaneous melanoma patients.


Sujet(s)
Régulation de l'expression des gènes tumoraux/immunologie , Cellules tueuses naturelles/immunologie , Mélanome/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Sous-famille K des récepteurs de cellules NK de type lectine/immunologie , Tumeurs cutanées/immunologie , Sujet âgé , Cytotoxicité immunologique , Femelle , Humains , Interféron alpha/pharmacologie , Interleukine-12/pharmacologie , Interleukine-18/pharmacologie , Interleukine-2/pharmacologie , Cellules K562 , Cellules tueuses naturelles/effets des médicaments et des substances chimiques , Cellules tueuses naturelles/anatomopathologie , Mâle , Mélanome/génétique , Mélanome/anatomopathologie , Adulte d'âge moyen , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Sous-famille K des récepteurs de cellules NK de type lectine/génétique , Stadification tumorale , Culture de cellules primaires , Appréciation des risques , Tumeurs cutanées/génétique , Tumeurs cutanées/anatomopathologie , Facteur de croissance transformant bêta-1/génétique , Facteur de croissance transformant bêta-1/immunologie ,
19.
Cell Mol Immunol ; 16(11): 868-877, 2019 11.
Article de Anglais | MEDLINE | ID: mdl-30275537

RÉSUMÉ

Helper-type innate lymphoid cells (ILC) play an important role in intestinal homeostasis. Members of the NKR-P1 gene family are expressed in various innate immune cells, including natural killer (NK) cells, and their cognate Clr ligand family members are expressed in various specialized tissues, including the intestinal epithelium, where they may play an important role in mucosal-associated innate immune responses. In this study, we show that the inhibitory NKR-P1B receptor, but not the Ly49 receptor, is expressed in gut-resident NK cells, ILC, and a subset of γδT cells in a tissue-specific manner. ILC3 cells constitute the predominant cell subset expressing NKR-P1B in the gut lamina propria. The known NKR-P1B ligand Clr-b is broadly expressed in gut-associated cells of hematopoietic origin. The genetic deletion of NKR-P1B results in a higher frequency and number of ILC3 and γδT cells in the gut lamina propria. However, the function of gut-resident ILC3, NK, and γδT cells in NKR-P1B-deficient mice is impaired during gastrointestinal tract infection by Citrobacter rodentium or Salmonella typhimurium, resulting in increased systemic bacterial dissemination in NKR-P1B-deficient mice. Our findings highlight the role of the NKR-P1B:Clr-b recognition system in the modulation of intestinal innate immune cell functions.


Sujet(s)
Citrobacter rodentium/immunologie , Infections à Enterobacteriaceae/immunologie , Immunité innée , Maladies intestinales/immunologie , Muqueuse intestinale/immunologie , Cellules tueuses naturelles/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Salmonelloses/immunologie , Salmonella typhimurium/immunologie , Lymphocytes T/immunologie , Animaux , Infections à Enterobacteriaceae/génétique , Infections à Enterobacteriaceae/anatomopathologie , Maladies intestinales/génétique , Maladies intestinales/microbiologie , Maladies intestinales/anatomopathologie , Muqueuse intestinale/microbiologie , Muqueuse intestinale/anatomopathologie , Cellules tueuses naturelles/anatomopathologie , Souris , Souris knockout , Sous-famille B des récepteurs de cellules NK de type lectine/génétique , Récepteur lymphocytaire T antigène, gamma-delta/immunologie , Salmonelloses/génétique , Salmonelloses/anatomopathologie , Lymphocytes T/anatomopathologie
20.
Nat Immunol ; 19(12): 1403-1414, 2018 12.
Article de Anglais | MEDLINE | ID: mdl-30397350

RÉSUMÉ

Repair of tissue damaged during inflammatory processes is key to the return of local homeostasis and restoration of epithelial integrity. Here we describe CD161+ regulatory T (Treg) cells as a distinct, highly suppressive population of Treg cells that mediate wound healing. These Treg cells were enriched in intestinal lamina propria, particularly in Crohn's disease. CD161+ Treg cells had an all-trans retinoic acid (ATRA)-regulated gene signature, and CD161 expression on Treg cells was induced by ATRA, which directly regulated the CD161 gene. CD161 was co-stimulatory, and ligation with the T cell antigen receptor induced cytokines that accelerated the wound healing of intestinal epithelial cells. We identified a transcription-factor network, including BACH2, RORγt, FOSL2, AP-1 and RUNX1, that controlled expression of the wound-healing program, and found a CD161+ Treg cell signature in Crohn's disease mucosa associated with reduced inflammation. These findings identify CD161+ Treg cells as a population involved in controlling the balance between inflammation and epithelial barrier healing in the gut.


Sujet(s)
Muqueuse intestinale/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , Sous-populations de lymphocytes T/immunologie , Lymphocytes T régulateurs/immunologie , Trétinoïne/immunologie , Cicatrisation de plaie/immunologie , Maladie de Crohn/immunologie , Humains
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