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1.
Nat Commun ; 12(1): 4452, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294713

RESUMO

Atherosclerosis-associated cardiovascular disease is one of the main causes of death and disability among patients with diabetes mellitus. However, little is known about the impact of S-nitrosylation in diabetes-accelerated atherosclerosis. Here, we show increased levels of S-nitrosylation of guanine nucleotide-binding protein G(i) subunit alpha-2 (SNO-GNAI2) at Cysteine 66 in coronary artery samples from diabetic patients with atherosclerosis, consistently with results from mice. Mechanistically, SNO-GNAI2 acted by coupling with CXCR5 to dephosphorylate the Hippo pathway kinase LATS1, thereby leading to nuclear translocation of YAP and promoting an inflammatory response in endothelial cells. Furthermore, Cys-mutant GNAI2 refractory to S-nitrosylation abrogated GNAI2-CXCR5 coupling, alleviated atherosclerosis in diabetic mice, restored Hippo activity, and reduced endothelial inflammation. In addition, we showed that melatonin treatment restored endothelial function and protected against diabetes-accelerated atherosclerosis by preventing GNAI2 S-nitrosylation. In conclusion, SNO-GNAI2 drives diabetes-accelerated atherosclerosis by coupling with CXCR5 and activating YAP-dependent endothelial inflammation, and reducing SNO-GNAI2 is an efficient strategy for alleviating diabetes-accelerated atherosclerosis.


Assuntos
Aterosclerose/etiologia , Aterosclerose/metabolismo , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Células Cultivadas , Cisteína/química , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/química , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Knockout , Mutagênese Sítio-Dirigida , Óxido Nítrico Sintase Tipo II/metabolismo , Compostos Nitrosos/química , Compostos Nitrosos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores CXCR5/deficiência , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Fatores de Transcrição/metabolismo
2.
Aging (Albany NY) ; 13(11): 15384-15399, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34114971

RESUMO

CXCR5 played critical roles in tumorigenesis and metastasis. Nevertheless, little was known about the involvement of CXCR5 in perineural invasion (PNI) of salivary adenoid cystic carcinoma (SACC). Here, we confirmed upregulation of CXCR5 in SACC specimens and cells and identified that CXCR5 exhibited a significant positive correlation with PNI. Functionally, knockdown of CXCR5 suppressed SACC cells migration, invasion and PNI ability, whereas CXCR5 overexpression displayed the opposite effects. Moreover, CXCR5 downregulated microRNA (miR)-187, which could competitively sponge S100A4. The PNI-inhibitory effect of CXCR5 knockdown or miR-187 overexpression could be reversed by elevated expression of S100A4. Conjointly, our data revealed that CXCR5 facilitated PNI through downregulating miR-187 to disinhibit S100A4 expression in SACC.


Assuntos
Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/patologia , MicroRNAs/metabolismo , Receptores CXCR5/metabolismo , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Sequência de Bases , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Diferenciação Celular/genética , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Modelos de Riscos Proporcionais , Células de Schwann/metabolismo , Células de Schwann/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nat Commun ; 12(1): 3080, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035252

RESUMO

Studies that examined an association between CD8+T and prognosis in gastric cancer are inconsistent, and a distinct population of CXCR5+CD8+T associated with better overall survival has been reported among various malignancies. Here, we show that the abundance of intratumoral CXCR5+CD8+T cells is associated with better overall survival in patients with gastric cancer. Patients with TNM II + III gastric cancer with higher intratumoral CXCR5+CD8+T cell infiltration are more likely to benefit from adjuvant chemotherapy. Microsatellite-unstable and Epstein-Barr virus positive tumors are enriched with CXCR5+CD8+T cells. Gastric cancer infiltrating CXCR5+CD8+T cells represent a specific subtype of stem-like CD8+T with effector memory feature. Identification of the clinical significance and phenotype of gastric cancer infiltrating CXCR5+CD8+T provides a roadmap for patient stratification and trials of targeted therapies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores CXCR5/imunologia , Neoplasias Gástricas/imunologia , Linfócitos T CD8-Positivos/metabolismo , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Estadiamento de Neoplasias , Prognóstico , Receptores CXCR5/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/terapia , Análise de Sobrevida , Resultado do Tratamento
4.
Eur J Immunol ; 51(7): 1860-1863, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33733501

RESUMO

BOB.1/OBF.1 expression regulates the transcription of direct and indirect target genes. We propose that BOB.1/OBF.1 affects CXCL13-CXCR5 signaling of LTinducer and LTorganizer cells during embryonic Peyer's patch organogenesis as well as of B cells and follicular dendritic cells during lymphocyte homing at postnatal stages of secondary lymphoid organ development.


Assuntos
Nódulos Linfáticos Agregados/metabolismo , Transativadores/deficiência , Transativadores/metabolismo , Animais , Linfócitos B , Quimiocina CXCL13/metabolismo , Células Dendríticas Foliculares/metabolismo , Camundongos , Organogênese/fisiologia , Receptores CXCR5/metabolismo
5.
Eur J Immunol ; 51(6): 1377-1389, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33728639

RESUMO

The Ig superfamily protein glycoprotein A33 (GPA33) has been implicated in immune dysregulation, but little is known about its expression in the immune compartment. Here, we comprehensively determined GPA33 expression patterns on human blood leukocyte subsets, using mass and flow cytometry. We found that GPA33 was expressed on fractions of B, dendritic, natural killer and innate lymphoid cells. Most prominent expression was found in the CD4+ T cell compartment. Naïve and CXCR5+ regulatory T cells were GPA33high , and naïve conventional CD4+ T cells expressed intermediate GPA33 levels. The expression pattern of GPA33 identified functional heterogeneity within the CD4+ central memory T cell (Tcm) population. GPA33+ CD4+ Tcm cells were fully undifferentiated, bona fide Tcm cells that lack immediate effector function, whereas GPA33- Tcm cells exhibited rapid effector functions and may represent an early stage of differentiation into effector/effector memory T cells before loss of CD62L. Expression of GPA33 in conventional CD4+ T cells suggests a role in localization and/or preservation of an undifferentiated state. These results form a basis to study the function of GPA33 and show it to be a useful marker to discriminate between different cellular subsets, especially in the CD4+ T cell lineage.


Assuntos
Biomarcadores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Leucócitos Mononucleares/imunologia , Glicoproteínas de Membrana/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Diferenciação Celular , Linhagem da Célula , Separação Celular , Citometria de Fluxo , Células HEK293 , Humanos , Imunidade Inata , Memória Imunológica , Glicoproteínas de Membrana/genética , Receptores CXCR5/metabolismo
6.
Neurochem Res ; 46(6): 1457-1469, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33742328

RESUMO

Spinal cord injury (SCI) is one of the main causes leading to neuropathic pain. Here, we aim to explore the molecular mechanism and function of lncRNA PVT1 in neuropathic pain induced by SCI. The expression of lncRNA PVT1, microRNA (miR) - 186-5p was measured via quantitative reverse transcription PCR (qRT-PCR), and the activation of astrocytes (labeled by GFAP) was detected by immunohistochemistry. Western blot was conducted to detect the expression of chemokine ligand 13 (CXCL13), chemokine receptor 5 (CXCR5), cyclooxygenase-2 (COX2), inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP) in spinal cord injury lesions. The levels of inflammatory cytokines (including IL-1ß and IL-6) and MDA in tissues were examined via Enzyme-linked immunosorbent assay (ELISA). In vitro experiments were also conducted in primary cultured astrocyte to explore the response of astrocyte to lipopolysaccharide (LPS). What's more, the PVT1-miR-186-5p interaction was verified via the dual luciferase activity assay and RNA immunoprecipitation (RIP) assay. The results demonstrated that the levels of PVT1, CXCL13 and CXCR5 were upregulated, while miR-186-5p were decreased in SCI rats' spinal cord and LPS-mediated astrocytes. In the SCI model, PVT1 depletion significantly alleviated neuropathic pain, astrocytic activation and reduced the expression of neuroinflammatory factors and proteins. The relevant mechanism studies confirmed that PVT1 is a competitive endogenous RNA (ceRNA) of miR-186-5p, targets and inhibits its expression and promotes the expression of CXCL13/CXCR5, while miR-186-5p targets CXCL13. In conclusion, inhibition of lncRNA PVT1 alleviates neuropathic pain in SCI rats by upregulating miR-186-5p and down-regulating CXCL13/CXCR5. The PVT1/miR-186-5p/CXCL13/CXCR5 axis can be used as a new therapeutic target for neuropathic pain.


Assuntos
Astrócitos/metabolismo , Quimiocina CXCL13/metabolismo , MicroRNAs/metabolismo , Neuralgia/terapia , RNA Longo não Codificante/metabolismo , Receptores CXCR5/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Hiperalgesia/etiologia , Hiperalgesia/metabolismo , Hiperalgesia/patologia , Hiperalgesia/terapia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , Lipopolissacarídeos/farmacologia , Masculino , Neuralgia/etiologia , Neuralgia/metabolismo , Neuralgia/patologia , RNA Longo não Codificante/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Regulação para Cima/fisiologia
7.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33669065

RESUMO

Immunosenescence is characterized by age-associated changes in immunological functions. Although age- and autoimmune-related sialadenitis cause dry mouth (xerostomia), the roles of immunosenescence and cellular senescence in the pathogenesis of sialadenitis remain unknown. We demonstrated that acquired immune cells rather than innate immune cells infiltrated the salivary glands (SG) of aged mice. An analysis of isolated epithelial cells from SG revealed that the expression levels of the chemokine CXCL13 were elevated in aged mice. Senescence-associated T cells (SA-Ts), which secrete large amounts of atypical pro-inflammatory cytokines, are involved in the pathogenesis of metabolic disorders and autoimmune diseases. The present results showed that SA-Ts and B cells, which express the CXCL13 receptor CXCR5, accumulated in the SG of aged mice, particularly females. CD4+ T cells derived from aged mice exhibited stronger in vitro migratory activity toward CXCL13 than those from young mice. In a mouse model of Sjögren's syndrome (SS), SA-Ts also accumulated in SG, presumably via CXCL12-CXCR4 signaling. Collectively, the present results indicate that SA-Ts accumulate in SG, contribute to the pathogenesis of age- and SS-related sialadenitis by up-regulating chemokines in epithelial cells, and have potential as therapeutic targets for the treatment of xerostomia caused by these types of sialadenitis.


Assuntos
Senescência Celular/imunologia , Quimiocinas/metabolismo , Células Epiteliais/metabolismo , Glândulas Salivares/metabolismo , Sialadenite/metabolismo , Síndrome de Sjogren/imunologia , Linfócitos T/metabolismo , Xerostomia/metabolismo , Animais , Doenças Autoimunes/metabolismo , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular/imunologia , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Quimiocinas/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Glândulas Salivares/citologia , Glândulas Salivares/imunologia , Sialadenite/patologia , Síndrome de Sjogren/patologia , Linfócitos T/imunologia , Xerostomia/patologia
8.
Arthritis Rheumatol ; 73(7): 1233-1243, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33538119

RESUMO

OBJECTIVE: Our aim was to compare transcriptome and phenotype profiles of CD4+ T cells and CD19+ B cells in patients with Takayasu arteritis (TAK), patients with giant cell arteritis (GCA), and healthy donors. METHODS: Gene expression analyses, flow cytometry immunophenotyping, T cell receptor (TCR) gene sequencing, and functional assessments of cells from peripheral blood and arterial lesions from TAK patients, GCA patients, and healthy donors were performed. RESULTS: Among the most significantly dysregulated genes in CD4+ T cells of TAK patients compared to GCA patients (n = 720 genes) and in CD4+ T cells of TAK patients compared to healthy donors (n = 1,447 genes), we identified a follicular helper T (Tfh) cell signature, which included CXCR5, CCR6, and CCL20 genes, that was transcriptionally up-regulated in TAK patients. Phenotypically, there was an increase in CD4+CXCR5+CCR6+CXCR3- Tfh17 cells in TAK patients that was associated with a significant enrichment of CD19+ B cell activation. Functionally, Tfh cells helped B cells to proliferate, differentiate into memory cells, and secrete IgG antibodies. Maturation of B cells was inhibited by JAK inhibitors. Locally, in areas of arterial inflammation, we found a higher proportion of tertiary lymphoid structures comprised CD4+, CXCR5+, programmed death 1+, and CD20+ cells in TAK patients compared to GCA patients. CD4+CXCR5+ T cells in the aortas of TAK patients had an oligoclonal α/ß TCR repertoire. CONCLUSION: We established the presence of a specific Tfh cell signature in both circulating and aorta-infiltrating CD4+ T cells from TAK patients. The cooperation of Tfh cells and B cells might be critical in the occurrence of vascular inflammation in patients with TAK.


Assuntos
Linfócitos B/imunologia , Arterite de Células Gigantes/imunologia , Células T Auxiliares Foliculares/imunologia , Arterite de Takayasu/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD19/metabolismo , Antígenos CD20/metabolismo , Aorta , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Arterite de Células Gigantes/genética , Humanos , Imunoglobulina G/metabolismo , Memória Imunológica , Imunofenotipagem , Inibidores de Janus Quinases/farmacologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Pirazóis/farmacologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/efeitos dos fármacos , Células T Auxiliares Foliculares/metabolismo , Arterite de Takayasu/genética , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/metabolismo , Estruturas Linfoides Terciárias/patologia , Transcriptoma
9.
Allergol Immunopathol (Madr) ; 49(2): 113-121, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33641302

RESUMO

BACKGROUND: Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hypermutations, and affinity maturation. OBJECTIVE: To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia. METHODS: We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed. RESULTS: In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups. CONCLUSIONS: A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency.


Assuntos
Agamaglobulinemia/diagnóstico , Imunodeficiência de Variável Comum/diagnóstico , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/imunologia , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Fatores Etários , Contagem de Linfócito CD4 , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Diagnóstico Diferencial , Feminino , Humanos , Imunidade Humoral , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Células T Auxiliares Foliculares/metabolismo
10.
Nat Commun ; 12(1): 1333, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637761

RESUMO

T follicular helper (TFH) cells are specialized effector CD4+ T cells critical to humoral immunity. Whether post-transcriptional regulation has a function in TFH cells is unknown. Here, we show conditional deletion of METTL3 (a methyltransferase catalyzing mRNA N6-methyladenosine (m6A) modification) in CD4+ T cells impairs TFH differentiation and germinal center responses in a cell-intrinsic manner in mice. METTL3 is necessary for expression of important TFH signature genes, including Tcf7, Bcl6, Icos and Cxcr5 and these effects depend on intact methyltransferase activity. m6A-miCLIP-seq shows the 3' UTR of Tcf7 mRNA is subjected to METTL3-dependent m6A modification. Loss of METTL3 or mutation of the Tcf7 3' UTR m6A site results in accelerated decay of Tcf7 transcripts. Importantly, ectopic expression of TCF-1 (encoded by Tcf7) rectifies TFH defects owing to METTL3 deficiency. Our findings indicate that METTL3 stabilizes Tcf7 transcripts via m6A modification to ensure activation of a TFH transcriptional program, indicating a pivotal function of post-transcriptional regulation in promoting TFH cell differentiation.


Assuntos
Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Metiltransferases/genética , Metiltransferases/metabolismo , Células T Auxiliares Foliculares/metabolismo , Animais , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Centro Germinativo/imunologia , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Ativação Linfocitária , Linfócitos Nulos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , RNA Mensageiro/metabolismo , Receptores CXCR5/metabolismo
11.
Aging Cell ; 20(1): e13295, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387451

RESUMO

Ageing profoundly changes our immune system and is thought to be a driving factor in the morbidity and mortality associated with infectious disease in older people. We have previously shown that the impaired immunity to vaccination that occurs in aged individuals is partly attributed to the effect of age on T follicular helper (Tfh) cell formation. In this study, we examined how age intrinsically affects Tfh cell formation in both mice and humans. We show increased formation of Tfh precursors (pre-Tfh) but no associated increase in germinal centre (GC)-Tfh cells in aged mice, suggesting age-driven promotion of only early Tfh cell differentiation. Mechanistically, we show that ageing alters TCR signalling which drives expression of the Notch-associated transcription factor, RBPJ. Genetic or chemical modulation of RBPJ or Notch rescues this age-associated early Tfh cell differentiation, and increased intrinsic Notch activity recapitulates this phenomenon in younger mice. Our data offer mechanistic insight into the age-induced changes in T-cell activation that affects the differentiation and ultimately the function of effector T cells.


Assuntos
Diferenciação Celular/imunologia , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Receptores CXCR5/metabolismo , Células T Auxiliares Foliculares/imunologia , Envelhecimento , Animais , Feminino , Humanos , Camundongos
12.
Nat Commun ; 12(1): 240, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431832

RESUMO

CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin's lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME.


Assuntos
Linfócitos B/imunologia , Linfoma não Hodgkin/imunologia , Neoplasias/imunologia , Receptores CXCR5/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Células HEK293 , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
13.
Eur J Immunol ; 51(5): 1289-1292, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33491181

RESUMO

Term and preterm neonates have very few circulating Tfh-like cells (cTfh), and no circulating Tfr-like cells. Neonatal cTfh are CXCR5lo PD-1lo CD45RAhi , suggestive of a naive, possibly recently activated phenotype. CXCL13 is high at birth, but decreases rapidly in the first weeks of life. Overall, signs of GC activity in human neonates are weak, even in those born prematurely or after sepsis.


Assuntos
Biomarcadores , Quimiocina CXCL13/metabolismo , Nascimento Prematuro/metabolismo , Receptores CXCR5/metabolismo , Nascimento a Termo/metabolismo , Suscetibilidade a Doenças , Humanos , Imunofenotipagem , Recém-Nascido , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
14.
Lab Invest ; 101(2): 228-244, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32994482

RESUMO

Homeostasis of the retinal pigment epithelium (RPE) is essential for the health and proper function of the retina. Regulation of RPE homeostasis is, however, largely unexplored, yet dysfunction of this process may lead to retinal degenerative diseases, including age-related macular degeneration (AMD). Here, we report that chemokine receptor CXCR5 regulates RPE homeostasis through PI3K/AKT signaling and by suppression of FOXO1 activation. We used primary RPE cells isolated from CXCR5-deficient mice and wild type controls, as well as ex vivo RPE-choroidal-scleral complexes (RCSC) to investigate the regulation of homeostasis. CXCR5 expression in mouse RPE cells was diminished by treatment with hydrogen peroxide. Lack of CXCR5 expression leads to an abnormal cellular shape, pigmentation, decreased expression of the RPE differentiation marker RPE65, an increase in the undifferentiated progenitor marker MITF, and compromised RPE barrier function, as well as compromised cell-to-cell interaction. An increase in epithelial-mesenchymal transition (EMT) markers (αSMA, N-cadherin, and vimentin) was noted in CXCR5-deficient RPE cells both in vitro and in age-progression specimens of CXCR5-/- mice (6, 12, 24-months old). Deregulated autophagy in CXCR5-deficient RPE cells was observed by decreased LC3B-II, increased p62, abnormal autophagosomes, and impaired lysosome enzymatic activity as shown by GFP-LC3-RFP reporter plasmid. Mechanistically, deficiency in CXCR5 resulted in the downregulation of PI3K and AKT signaling, but upregulation and nuclear localization of FOXO1. Additionally, inhibition of PI3K in RPE cells resulted in an increased expression of FOXO1. Inhibition of FOXO1, however, reverts the degradation of ZO-1 caused by CXCR5 deficiency. Collectively, these findings suggest that CXCR5 maintains PI3K/AKT signaling, which controls FOXO1 activation, thereby regulating the expression of genes involved in RPE EMT and autophagy deregulation.


Assuntos
Receptores CXCR5 , Epitélio Pigmentado da Retina , Animais , Autofagia/genética , Células Cultivadas , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Receptores CXCR5/fisiologia , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/fisiopatologia , Transdução de Sinais/genética
15.
Mod Rheumatol ; 31(1): 249-260, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32023137

RESUMO

OBJECTIVES: The aim of this study was to determine pathological features of T peripheral helper (Tph)-like (PD-1+CXCR5-CD4+ T) cells in IgG4-related disease (IgG4-RD). METHODS: Tph-like cells in the blood and submandibular glands (SMGs) from IgG4-RD patients were analyzed by flow cytometry. Correlations between level of a Tph-like cell subset and clinical parameters of IgG4-RD were investigated. The cytotoxic capacity of Tph-like cells was also examined. Expression profiles of a molecule related to a Tph-like cell subset in IgG4-RD SMGs were assessed by immunohistochemistry. RESULTS: Tph-like cells from IgG4-RD patients highly expressed a fractalkine receptor, CX3CR1. Percentages of circulating CX3CR1+ Tph-like cells were significantly correlated with clinical parameters including IgG4-RD Responder Index, number of involved organs, and serum level of soluble IL-2 receptor. CX3CR1+ Tph-like cells abundantly possessed cytotoxic T lymphocyte-related molecules such as granzyme A, perforin, and G protein-coupled receptor 56. Functional assays revealed their cytotoxic potential against vascular endothelial cells and ductal epithelial cells. Immunohistochemistry showed that fractalkine was markedly expressed in vascular endothelial cells and ductal epithelial cells in IgG4-RD SMGs. CONCLUSION: CX3CR1+ Tph-like cells are thought to contribute to persistent tissue injury in IgG4-RD and are a potential clinical marker and/or therapeutic target for inhibiting progression of IgG4-RD.


Assuntos
Endotélio Vascular/patologia , Doença Relacionada a Imunoglobulina G4/imunologia , Linfócitos T Citotóxicos/imunologia , Células Endoteliais/patologia , Endotélio Vascular/imunologia , Feminino , Granzimas/metabolismo , Humanos , Doença Relacionada a Imunoglobulina G4/patologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/metabolismo , Glândula Submandibular/metabolismo
16.
Front Immunol ; 11: 559866, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33133070

RESUMO

Fibroblastic reticular cells (FRCs) are the specialized lymphoid stromal cells initially identified as triggering T-cell recruitment and dynamic motion in secondary lymphoid organs. Interestingly, FRCs also display antigen presentation capacities and support lymphocyte survival. CXCR5+CD4+ follicular T cells are important players of B-cell maturation and antibody response. Our study reported that in vitro-differentiated FRC-like cells enhanced the growth of the whole CXCR5+CD4+ T-cell compartment, while enhancing IL-4 secretion specifically by the PD1dimCXCR5+CD4+ cell subset, in a Notch- and ICAM1/LFA1-dependent manner. In addition, we revealed that in follicular lymphoma (FL) tissues, previously identified as enriched for PD1hiCXCR5hiCD4+ mature follicular helper T cells, PD1dimCXCR5+CD4+ T cells displayed an enrichment for Notch and integrin gene signatures, and a Notch and ICAM-1-dependent overexpression of IL-4 compared to their non-malignant counterparts. These findings suggest that the crosstalk between FRCs and CXCR5+PD1dimCD4+ T cells may contribute to the FL IL-4 rich environment, thus providing new insights in FL lymphomagenesis.


Assuntos
Interleucina-4/biossíntese , Ativação Linfocitária/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/fisiologia , Células Estromais/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Biomarcadores , Comunicação Celular , Proliferação de Células , Sobrevivência Celular , Citocinas/biossíntese , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Molécula 1 de Adesão Intercelular/metabolismo , Ativação Linfocitária/genética , Receptores CXCR5/metabolismo , Receptores Notch/metabolismo , Transcriptoma
17.
Front Immunol ; 11: 2134, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013901

RESUMO

Natural killer (NK) cells play essential roles in immunity to viruses and tumors. Their function is genetically determined but also modulated by environmental factors. The distribution and functional regulation of these cells vary depending on the tissue. NK cell behavior in lymphoid tissues is so far understudied. Non-human primate (NHP) models are essential for the development of therapies and vaccines against human diseases, and access to NHP tissues allows insights into spatial regulations of NK cells. Here, we investigated tissue-specific parameters of NK cells from NHP species, i.e., cynomolgus macaque (Macaca fascicularis), African green monkey (Chlorocebus sabaeus), rhesus macaque (Macaca mulatta), and baboon (Papio anubis). By comprehensive multi-dimensional analysis of NK cells from secondary lymphoid organs, intestinal mucosa, liver, and blood, we identified tissue- and species-specific patterns of NK cell frequencies, phenotypes, and potential activity. Also, we defined the tissue-specific characteristics of NK cells during infection by the simian immunodeficiency virus. Altogether, our results provide a comprehensive anatomic analysis of NK cells in different tissues of primates at steady-state and during a viral infection.


Assuntos
Síndrome de Imunodeficiência Adquirida/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Células Matadoras Naturais/imunologia , Tecido Linfoide/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Animais , Células Cultivadas , Humanos , Imunofenotipagem , Receptor 2 Desencadeador da Citotoxicidade Natural/metabolismo , Especificidade de Órgãos , Primatas , Receptores CXCR5/metabolismo , Especificidade da Espécie
18.
Front Immunol ; 11: 561404, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123134

RESUMO

Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or ß-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.


Assuntos
Quimiocinas CXC/metabolismo , Quimiotaxia/imunologia , Homeostase/imunologia , Receptores CCR7/metabolismo , Receptores CXCR4/metabolismo , Receptores CXCR5/metabolismo , Transdução de Sinais/imunologia , Doadores de Sangue , Cálcio/metabolismo , Quimiocina CCL19/metabolismo , Quimiocina CCL21/metabolismo , Quimiocina CXCL13/metabolismo , Quimiotaxia/genética , Células HEK293 , Homeostase/genética , Humanos , Ligação Proteica , Receptores CCR7/genética , Receptores CXCR4/genética , Receptores CXCR5/genética , Transdução de Sinais/genética , Linfócitos T/imunologia , Transfecção , beta-Arrestina 2/metabolismo
19.
Proc Natl Acad Sci U S A ; 117(46): 28960-28970, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33127761

RESUMO

Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.


Assuntos
Neoplasias Colorretais/metabolismo , Imunidade/imunologia , Pâncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores CXCR4/efeitos dos fármacos , Receptores CXCR4/metabolismo , Idoso , Carcinoma Ductal Pancreático , Quimiocina CXCL12 , Neoplasias Colorretais/patologia , Feminino , Compostos Heterocíclicos/antagonistas & inibidores , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/patologia , Receptores CCR2/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR5/metabolismo , Receptores CXCR6/metabolismo , Receptores de Interleucina-8A/metabolismo , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/imunologia
20.
Sci Rep ; 10(1): 15686, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973217

RESUMO

Monitoring the frequency of circulatory CXCR5+ (cCXCR5+) CD4+ T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (TFH) activity within germinal center. However, cCXCR5+ T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5+ T cell following yellow fever immunization. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38+ICOS+PD1+, but then transitioned to become CD38+ICOS-PD1+ and CD38-ICOS-PD1+ before coming to rest as a CD38-ICOS-PD1- subset. These results imply that most antigen-specific cCXCR5+ T cells, including the CD38-ICOS-PD1- CXCR5+ T cells are derived from the CXCR5+CD38+ICOS+PD1+ subset, the subset that most resembles preTFH/TFH in the germinal center.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinação , Vacina contra Febre Amarela/imunologia , Febre Amarela/prevenção & controle , Linfócitos T CD4-Positivos/metabolismo , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Receptores CXCR5/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
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