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1.
Signal Transduct Target Ther ; 6(1): 328, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471088

RESUMO

Understanding the pathological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in an animal model is crucial for the treatment of coronavirus disease 2019 (COVID-19). Here, we compared immunopathological changes in young and old rhesus macaques (RMs) before and after SARS-CoV-2 infection at the tissue level. Quantitative analysis of multiplex immunofluorescence staining images of formalin-fixed paraffin-embedded (FFPE) sections showed that SARS-CoV-2 infection specifically induced elevated levels of apoptosis, autophagy, and nuclear factor kappa-B (NF-κB) activation of angiotensin-converting enzyme 2 (ACE2)+ cells, and increased interferon α (IFN-α)- and interleukin 6 (IL-6)-secreting cells and C-X-C motif chemokine receptor 3 (CXCR3)+ cells in lung tissue of old RMs. This pathological pattern, which may be related to the age-related pro-inflammatory microenvironment in both lungs and spleens, was significantly correlated with the systemic accumulation of CXCR3+ cells in lungs, spleens, and peripheral blood. Furthermore, the ratio of CXCR3+ to T-box protein expression in T cell (T-bet)+ (CXCR3+/T-bet+ ratio) in CD8+ cells may be used as a predictor of severe COVID-19. These findings uncovered the impact of aging on the immunopathology of early SARS-CoV-2 infection and demonstrated the potential application of CXCR3+ cells in predicting severe COVID-19.


Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Microambiente Celular/imunologia , Pulmão/imunologia , Receptores CXCR3/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , COVID-19/patologia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/patologia , Interferon-alfa/imunologia , Interleucina-6/imunologia , Pulmão/patologia , Pulmão/virologia , Macaca mulatta , Masculino
2.
JCI Insight ; 6(18)2021 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-34283810

RESUMO

The importance of the adaptive T cell response in the control and resolution of viral infection has been well established. However, the nature of T cell-mediated viral control mechanisms in life-threatening stages of COVID-19 has yet to be determined. The aim of the present study was to determine the function and phenotype of T cell populations associated with survival or death of patients with COVID-19 in intensive care as a result of phenotypic and functional profiling by mass cytometry. Increased frequencies of circulating, polyfunctional CD4+CXCR5+HLA-DR+ stem cell memory T cells (Tscms) and decreased proportions of granzyme B-expressing and perforin-expressing effector memory T cells were detected in recovered and deceased patients, respectively. The higher abundance of polyfunctional PD-L1+CXCR3+CD8+ effector T cells (Teffs), CXCR5+HLA-DR+ Tscms, and anti-nucleocapsid (anti-NC) cytokine-producing T cells permitted us to differentiate between recovered and deceased patients. The results from a principal component analysis show an imbalance in the T cell compartment that allowed for the separation of recovered and deceased patients. The paucity of circulating PD-L1+CXCR3+CD8+ Teffs and NC-specific CD8+ T cells accurately forecasts fatal disease outcome. This study provides insight into the nature of the T cell populations involved in the control of COVID-19 and therefore might impact T cell-based vaccine designs for this infectious disease.


Assuntos
Antígeno B7-H1/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Imunidade Celular , Receptores CXCR3/imunologia , Adulto , COVID-19/mortalidade , COVID-19/patologia , Epitopos de Linfócito T/imunologia , Feminino , França/epidemiologia , Humanos , Memória Imunológica , Ativação Linfocitária , Masculino , SARS-CoV-2 , Taxa de Sobrevida/tendências
3.
Elife ; 102021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34328416

RESUMO

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation, and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor-promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis, and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.


Assuntos
Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Inflamação/etiologia , Neoplasias Pancreáticas/fisiopatologia , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo , Microambiente Tumoral/imunologia , Animais , Células Cultivadas , Quimiocina CXCL10/antagonistas & inibidores , Quimiocina CXCL10/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Inflamação/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Pâncreas/citologia , Pâncreas/imunologia , Pâncreas/patologia , Neoplasias Pancreáticas/imunologia , Receptores CXCR3/antagonistas & inibidores , Receptores CXCR3/genética , Transdução de Sinais
4.
Nat Commun ; 12(1): 2715, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976157

RESUMO

Efficient immune responses rely on heterogeneity, which in CD8+ T cells, amongst other mechanisms, is achieved by asymmetric cell division (ACD). Here we find that ageing, known to negatively impact immune responses, impairs ACD in murine CD8+ T cells, and that this phenotype can be rescued by transient mTOR inhibition. Increased ACD rates in mitotic cells from aged mice restore the expansion and memory potential of their cellular progenies. Further characterization of the composition of CD8+ T cells reveals that virtual memory cells (TVM cells), which accumulate during ageing, have a unique proliferation and metabolic profile, and retain their ability to divide asymmetrically, which correlates with increased memory potential. The opposite is observed for naive CD8+ T cells from aged mice. Our data provide evidence on how ACD modulation contributes to long-term survival and function of T cells during ageing, offering new insights into how the immune system adapts to ageing.


Assuntos
Envelhecimento/genética , Divisão Celular Assimétrica/genética , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/genética , Serina-Treonina Quinases TOR/genética , Envelhecimento/imunologia , Animais , Divisão Celular Assimétrica/imunologia , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Imunidade Inata , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ativação Linfocitária , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/imunologia
5.
Eur J Immunol ; 51(8): 2040-2050, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33963550

RESUMO

New ways of characterizing CD8+ memory T cell responses in chronic infections are based on the measurement of chemokine receptor expression (CXCR3, CXCR5, and CX3CR1). We applied these novel phenotyping strategies to chronic HIV infection by comparing healthy donors (HDs), HIV-infected patients receiving antiretroviral therapy (ART), and spontaneous HIV controllers (HICs). In all groups, the memory cells exhibited high proportion of CXCR3+ cells. Proportions of CXCR5+ and CX3CR1+ cells were preferentially observed among central memory cells (Tcm) and effector memory cells (Tem) respectively. Chronic controlled HIV infection impacted the chemokine receptor profile of both HIV-specific and nonspecific CD8+ T cells. In total CD8+ T cells, the proportions of CXCR3- CXCR5- CX3CR1- Tcm and Tem were lower in HIV-infected patients than in HDs with subtle differences between ART and HICs. Such phenotyping strategy also revealed differences in exhaustion and senescence phenotypes, the CXCR3+ CXCR5+ CX3CR1- being more exhausted and senescent than the CXCR3+ CXCR5- CX3CR1- Tcm fraction. Among HIV-specific CD8+ T cells, the vast majority of Tcm cells were CXCR3+ and CXCR5+ cells in contrast with their nonspecific counterparts. In conclusion, the addition of migration markers contributes to better characterize Tcm/Tem compartment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Memória Imunológica/imunologia , Receptores CXCR3/imunologia , Receptores CXCR5/imunologia , Adulto , Feminino , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/imunologia
6.
Int J Mol Sci ; 22(7)2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33916486

RESUMO

Type I interferons (IFNs) are required for spontaneous lacrimal gland inflammation in the nonobese diabetic (NOD) mouse model of Sjögren's disease, but the consequences of type I IFN signaling are not well-defined. Here, we use RNA sequencing to define cytokine and chemokine genes upregulated in lacrimal glands of NOD mice in a type I IFN-dependent manner. Interleukin (IL)-21 was the highest differentially expressed cytokine gene, and Il21 knockout NOD mice were relatively protected from lacrimal gland inflammation. We defined a set of chemokines upregulated early in disease including Cxcl9 and Cxcl10, which share a receptor, CXCR3. CXCR3+ T cells were enriched in lacrimal glands with a dominant proportion of CXCR3+ regulatory T cells. Together these data define the early cytokine and chemokine signals associated with type I IFN-signaling in the development of lacrimal gland inflammation in NOD mice providing insight into the role of type I IFN in autoimmunity development.


Assuntos
Quimiocina CXCL10/imunologia , Quimiocina CXCL9/imunologia , Interleucinas/imunologia , Aparelho Lacrimal/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Interleucinas/genética , Aparelho Lacrimal/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Transdução de Sinais/genética , Linfócitos T Reguladores/patologia
7.
Int J Mol Sci ; 22(5)2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33807704

RESUMO

Alopecia areata (AA) is regarded as a tissue-specific and cell-mediated autoimmune disorder. Regarding the cytokine balance, AA has been considered a type 1 inflammatory disease. On the other hand, AA often complicates atopic dermatitis (AD) and AD is regarded as type 2 inflammatory disease. However, the immunological aspects of AA in relation to AD are still poorly understood. Therefore, we aim to clarify the immunological properties of AD-associated AA. In this study, we performed comparative analysis of the expression of intracytoplasmic cytokines (IFN-γ, IL-4, and IL-13), chemokine receptors (CXCR3 and CCR4) in peripheral blood which were taken from healthy controls, non-atopic AA patients, AA patients with extrinsic AD, and AA patients with intrinsic AD by flowcytometric analysis. We also compared the scalp skin samples taken from AA patients with extrinsic AD before and after treatment with dupilumab. In non-atopic AA patients, the ratios of CD4+IFN-γ+ cells to CD4+IL-4+ cells and CD4+IFN-γ+ cells to CD4+IL-13+ cells were higher than those in AA patients with extrinsic AD. Meanwhile, the ratio of CD8+IFN-γ+ cells to CD8+IL-13+ cells was significantly higher in the non-atopic AA than in the healthy controls. In AA patients with extrinsic AD, the skin AA lesion showed dense infiltration of not only CXCR3+ cells but also CCR4+ cells around hair bulb before dupilumab treatment. However, after the treatment, the number of CXCR3+ cells had no remarkable change while the number of CCR4+ cells significantly decreased. These results indicate that the immunological condition of AA may be different between atopic and non-atopic patients and between extrinsic and intrinsic AD patients. Our study provides an important notion that type 2 immunity may participate in the development of AA in extrinsic AD patients. It may be considered that the immunological state of non-atopic AA is different from that of atopic AA.


Assuntos
Alopecia em Áreas/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Dermatite Atópica/imunologia , Adulto , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Receptores CCR4/imunologia , Receptores CXCR3/imunologia , Adulto Jovem
8.
Eur J Immunol ; 51(7): 1732-1747, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33844287

RESUMO

Long-lived T-memory stem cells (TSCM ) are key to both naturally occurring and vaccine-conferred protection against infection. These cells are characterized by the CD45RA+ CCR7+ CD95+ phenotype. Significant heterogeneity within the TSCM population is recognized, but distinguishing surface markers and functional characterization of potential subsets are lacking. Human CD8 TSCM subsets were identified in healthy subjects who had been previously exposed to CMV or Influenza (Flu) virus in flow cytometry by expression of CD122 or CXCR3, and then characterized in proliferation, multipotency, self-renewal, and intracellular cytokine production (TNF-α, IL-2, IFN-γ), together with transcriptomic profiles. The TSCM CD122hi -expressing subset (versus CD122lo ) demonstrated greater proliferation, greater multipotency, and enhanced polyfunctionality with higher frequencies of triple positive (TNF-α, IL-2, IFN-γ) cytokine-producing cells upon exposure to recall antigen. The TSCM CXCR3lo subpopulation also had increased proliferation and polyfunctional cytokine production. Transcriptomic analysis further showed that the TSCM CD122hi population had increased expression of activation and homing molecules, such as Ccr6, Cxcr6, Il12rb, and Il18rap, and downregulated cell proliferation inhibitors, S100A8 and S100A9. These data reveal that the TSCM CD122hi phenotype is associated with increased proliferation, enhanced multipotency and polyfunctionality with an activated memory-cell like transcriptional profile, and hence, may be favored for induction by immunization and for adoptive immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Subunidade beta de Receptor de Interleucina-2/imunologia , Receptores CXCR3/imunologia , Antígenos/imunologia , Citocinas/imunologia , Humanos , Imunoterapia Adotiva/métodos , Fenótipo , Células-Tronco/imunologia
9.
Clin Immunol ; 226: 108717, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33775870

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, and the etiopathogenesis is unclear. Follicular helper T (Tfh) cells have been reported as an important pathogenic cell type in SLE. CXCR3 was reported to be decreased on lupus peripheral CD4+T cells. However, the expression level of CCR4, CCR6 and CXCR3 on Tfh-like cells in SLE peripheral blood and skin lesions is unknown. In this study, we detected CCR4, CCR6 and CXCR3 expression level on Tfh-like cells in the peripheral blood and skin lesions from SLE patients and normal controls (NCs). A decreased expression level of CXCR3 on Tfh-like cells was found in lupus peripheral blood. However, an increased CXCR3 expression was observed on total CD4+T and Tfh-like cells from lupus skin lesions. Moreover, we observed a higher expression level of CXCR3 in Tfh cells from human tonsils. These findings indicate that CXCR3 might help Tfh-like cells to migrate into the inflammatory sites.


Assuntos
Lúpus Eritematoso Sistêmico/imunologia , Receptores CXCR3/imunologia , Dermatopatias/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/imunologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores CCR4/imunologia , Receptores CCR6/imunologia , Adulto Jovem
10.
Int J Oncol ; 58(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33655329

RESUMO

Exposure of human immune cells to asbestos causes a reduction in antitumor immunity. The present study aimed to investigate the recovery of reduced antitumor immunity by several ingredients taken as supplements or foods, including trehalose (Treh) and glycosylated hesperidin (gHesp). Peripheral blood CD4+ cells were stimulated with IL­2, anti­CD3 and anti­CD28 antibodies for 3 days, followed by further stimulation with IL­2 for 7 days. Subsequently, cells were stimulated with IL­2 for an additional 28 days. During the 28 days, cells were cultured in the absence or presence of 50 µg/ml chrysotile asbestos fibers. In addition, cells were treated with 10 mM Treh or 10 µM gHesp. Following culture for 28 days, reverse transcription­quantitative PCR was performed to assess the expression levels of transcription factors, cytokines and specific genes, including matrix metalloproteinase­7 (MMP­7), nicotinamide nucleotide transhydrogenase (NNT) and C­X­C motif chemokine receptor 3, in unstimulated cells (fresh) and cells stimulated with PMA and ionomycin (stimuli). The results demonstrated that compared with the control group, chrysotile­exposure induced alterations in MMP­7, NNT and IL­17A expression levels were not observed in the 'Treh' and 'gHesp' groups in stimulated cells. The results suggested that Treh and gHesp may reverse asbestos exposure­induced reduced antitumor immunity in T helper cells. However, further investigation is required to confirm the efficacy of future trials involving the use of these compounds with high­risk human populations exposed to asbestos, such as workers involved in asbestos­handling activities.


Assuntos
Asbestos/efeitos adversos , Linfócitos T CD4-Positivos/imunologia , Suplementos Nutricionais , Hesperidina/farmacologia , Mesotelioma Maligno/imunologia , Trealose/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Masculino , Mesotelioma Maligno/induzido quimicamente , Mesotelioma Maligno/prevenção & controle , Pessoa de Meia-Idade , Receptores CXCR3/imunologia
11.
J Clin Invest ; 131(4)2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33586672

RESUMO

Estrogen deficiency causes a gut microbiome-dependent expansion of BM Th17 cells and TNF-α-producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1-mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.


Assuntos
Movimento Celular/imunologia , Intestinos , Osteoporose Pós-Menopausa , Ovariectomia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Quimiocina CCL20/genética , Quimiocina CCL20/imunologia , Feminino , Humanos , Intestinos/imunologia , Intestinos/microbiologia , Camundongos , Camundongos Knockout , Osteoporose Pós-Menopausa/imunologia , Osteoporose Pós-Menopausa/microbiologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Fator de Necrose Tumoral alfa/genética
12.
J Exp Med ; 218(5)2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33630019

RESUMO

Congenital human cytomegalovirus (cHCMV) infection of the brain is associated with a wide range of neurocognitive sequelae. Using infection of newborn mice with mouse cytomegalovirus (MCMV) as a reliable model that recapitulates many aspects of cHCMV infection, including disseminated infection, CNS infection, altered neurodevelopment, and sensorineural hearing loss, we have previously shown that mitigation of inflammation prevented alterations in cerebellar development, suggesting that host inflammatory factors are key drivers of neurodevelopmental defects. Here, we show that MCMV infection causes a dramatic increase in the expression of the microglia-derived chemokines CXCL9/CXCL10, which recruit NK and ILC1 cells into the brain in a CXCR3-dependent manner. Surprisingly, brain-infiltrating innate immune cells not only were unable to control virus infection in the brain but also orchestrated pathological inflammatory responses, which lead to delays in cerebellar morphogenesis. Our results identify NK and ILC1 cells as the major mediators of immunopathology in response to virus infection in the developing CNS, which can be prevented by anti-IFN-γ antibodies.


Assuntos
Encéfalo/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Linfócitos/imunologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Encéfalo/virologia , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocina CXCL9/metabolismo , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/virologia , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/genética , Inflamação/virologia , Células Matadoras Naturais/metabolismo , Linfócitos/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/imunologia , Microglia/metabolismo , Microglia/virologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Receptores CXCR3/metabolismo
13.
Mol Immunol ; 131: 112-120, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33446393

RESUMO

BACKGROUND: Networks formed of numerous autoantibodies (aabs) directed against G-protein coupled receptors (GPCR) have been suggested to play important role in autoimmune disorders. In present study, we aimed to evaluate the association between anti-GPCR antibodies and primary Sjogren's syndrome (pSS) to determine the potential pathogenic factors. METHODS: By applying a cell membrane-based ELISA technique, which is capable of detecting aabs against conformational epitopes within GPCR, serum levels of fourteen GPCR were determined in well-characterized patients with pSS (n = 52) and gender-matched healthy controls (n = 54). Comparisons between groups were analyzed by two-tailed Mann-Whitney U test, Bonferroni correction was applied for multiple comparisons. Spearman`s rank correlation coefficients were calculated between variables and visualized by heat map. RESULTS: Compared to healthy subjects, sera of patients with pSS showed significantly higher binding to ß2AR and ETAR, but lower binding to C5aR1, C3aR1, CXCR3, and CXCR4. Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 were also decreased in patients with rheumatoid arthritis. In pSS patients, levels of anti-CXCR3 and anti-CXCR4 antibodies were negatively correlated with circulating lymphocyte counts. Furthermore, correlation signatures of anti-GPCR antibodies changed dramatically in the patients with pulmonary involvement. CONCLUSIONS: This study demonstrates an association between pSS and autoantibodies recognizing GPCR, especially those functionally involved in immune cell migration and exocrine glandular secretion.


Assuntos
Autoanticorpos/imunologia , Receptor da Anafilatoxina C5a/imunologia , Receptores CXCR3/imunologia , Receptores CXCR4/imunologia , Receptores de Complemento/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Animais , Artrite Reumatoide/imunologia , Células CHO , Estudos de Casos e Controles , Cricetulus , Feminino , Humanos , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade
14.
Eur J Immunol ; 51(3): 626-633, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33152118

RESUMO

Epstein-Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3-expressing B cells preferentially infiltrate the CNS of MS patients. In chronic virus-infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B-cell subsets from MS patients who received autologous bone marrow transplantation (n = 9), which is often accompanied by EBV reactivation. The frequencies of nonclass-switched and class-switched memory B cells were reduced at 3-7 months, while only class-switched B cells returned back to baseline at 24-36 months posttransplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+ , and not CXCR4+ or CXCR5+ , class-switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti-VLA-4 antibody n = 15), latent EBV infection corresponded to enhanced in vitro formation of anti-EBNA1 IgG-secreting plasma cells under GC-like conditions. These findings imply that EBV persistence in B cells potentiates brain-homing and antibody-producing CXCR3+ subsets in MS.


Assuntos
Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Esclerose Múltipla/imunologia , Receptores CXCR3/imunologia , Células 3T3 , Animais , Formação de Anticorpos/imunologia , Encéfalo/imunologia , Células Cultivadas , Humanos , Imunoterapia/métodos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/imunologia , Camundongos , Receptores CXCR4/imunologia , Receptores CXCR5/imunologia
15.
Arthritis Rheumatol ; 73(5): 875-884, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33264510

RESUMO

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The predominant subtypes, oligoarticular and polyarticular JIA, are traditionally considered to be autoimmune diseases with a central role for T cells and autoantibodies. Mounting evidence suggests an important role for neutrophils in JIA pathogenesis. We undertook this study to investigate the phenotypic features of neutrophils present in the blood and inflamed joints of patients. METHODS: JIA synovial fluid (SF) and parallel blood samples from JIA patients and healthy children were collected. SF-treated neutrophils from healthy donors and pleural neutrophils from patients with pleural effusion were investigated as controls for SF exposure and extravasation. Multicolor flow cytometry panels allowed for in-depth phenotypic analysis of neutrophils, focusing on the expression of adhesion molecules, activation, and maturation markers and chemoattractant receptors. Multiplex technology was used to quantify cytokines in plasma and SF. RESULTS: SF neutrophils displayed an activated, hypersegmented phenotype with decreased CD62L expression, up-regulation of adhesion molecules CD66b, CD11b, and CD15, and down-regulation of CXCR1/2. An elevated percentage of CXCR4-positive neutrophils was detected in SF from patients. Pleural neutrophils showed less pronounced maturation differences. Strikingly, significant percentages of SF neutrophils showed a profound up-regulation of atypical neutrophil markers, including CXCR3, intercellular adhesion molecule 1, and HLA-DR. CONCLUSION: Our data show that neutrophils in inflamed joints of JIA patients have an activated phenotype. This detailed molecular analysis supports the notion that a complex intertwining between these innate immune cells and adaptive immune events drives JIA.


Assuntos
Artrite Juvenil/imunologia , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Receptores CXCR3/imunologia , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8B/imunologia , Líquido Sinovial/citologia , Imunidade Adaptativa/imunologia , Adolescente , Antígenos CD/metabolismo , Artrite Juvenil/metabolismo , Antígeno CD11b/metabolismo , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Criança , Pré-Escolar , Regulação para Baixo , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Antígenos HLA-DR/imunologia , Humanos , Imunidade Inata/imunologia , Imunofenotipagem , Molécula 1 de Adesão Intercelular/metabolismo , Selectina L/imunologia , Antígenos CD15/metabolismo , Masculino , Neutrófilos/metabolismo , Derrame Pleural , Regulação para Cima
16.
Infect Immun ; 89(2)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33199353

RESUMO

Toxoplasmosis is a worldwide zoonosis caused by the obligate intracellular parasite Toxoplasma gondii The symptoms of congenital toxoplasmosis range from embryonic death and resorption to subclinical infection, but the mechanism of disease onset remains unclear. C-X-C motif chemokine receptor 3 (CXCR3) is highly expressed in Th1-associated immune cells and plays an important role in the trafficking and activation of immune cells. However, the roles of CXCR3 in T. gondii-induced fetal loss and the molecular mechanism of embryo resorption remain poorly understood. In this study, we investigated the role of CXCR3 in fetal wastage caused by T. gondii infection using CXCR3-deficient (CXCR3-/-) mice. CXCR3-/- and wild-type pregnant mice were inoculated intraperitoneally with T. gondii tachyzoites on day 3.5 of gestation (Gd3.5). Pregnancy rates decreased as the pregnancy progressed in both infected groups; however, infected CXCR3-/- mice showed a significant fetal loss at Gd13.5 compared with that at Gd7.5. All embryos of the infected groups showed necrosis, and embryo resorption was significantly increased in infected CXCR3-/- compared with wild-type mice at Gd13.5. The parasite load of fetoplacental tissues was significantly increased in CXCR3-/- mice at Gd10.5. Moreover, mRNA expression levels of inducible nitric oxide synthase were significantly increased in fetoplacental tissues from infected wild-type mice compared to infected CXCR3-/- mice following the infection. These results suggested that CXCR3-dependent immune responses provide anti-Toxoplasma activity and play an essential role in reducing embryo resorption and fetal loss caused by T. gondii infection during early pregnancy.


Assuntos
Perda do Embrião/patologia , Feto/patologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/patologia , Receptores CXCR3/imunologia , Toxoplasma/imunologia , Toxoplasma/patogenicidade , Toxoplasmose/imunologia , Adulto , Animais , Modelos Animais de Doenças , Feminino , Mortalidade Fetal , Humanos , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II , Gravidez
17.
Nat Microbiol ; 6(1): 51-58, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33199863

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1-3 and individuals with COVID-19 have symptoms that can be asymptomatic, mild, moderate or severe4,5. In the early phase of infection, T- and B-cell counts are substantially decreased6,7; however, IgM8-11 and IgG12-14 are detectable within 14 d after symptom onset. In COVID-19-convalescent individuals, spike-specific neutralizing antibodies are variable3,15,16. No specific drug or vaccine is available for COVID-19 at the time of writing; however, patients benefit from treatment with serum from COVID-19-convalescent individuals17,18. Nevertheless, antibody responses and cross-reactivity with other coronaviruses in COVID-19-convalescent individuals are largely unknown. Here, we show that the majority of COVID-19-convalescent individuals maintained SARS-CoV-2 spike S1- and S2-specific antibodies with neutralizing activity against the SARS-CoV-2 pseudotyped virus, and that some of the antibodies cross-neutralized SARS-CoV, Middle East respiratory syndrome coronavirus or both pseudotyped viruses. Convalescent individuals who experienced severe COVID-19 showed higher neutralizing antibody titres, a faster increase in lymphocyte counts and a higher frequency of CXCR3+ T follicular help (TFH) cells compared with COVID-19-convalescent individuals who experienced non-severe disease. Circulating TFH cells were spike specific and functional, and the frequencies of CXCR3+ TFH cells were positively associated with neutralizing antibody titres in COVID-19-convalescent individuals. No individuals had detectable autoantibodies. These findings provide insights into neutralizing antibody responses in COVID-19-convalescent individuals and facilitate the treatment and vaccine development for SARS-CoV-2 infection.


Assuntos
Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Amplamente Neutralizantes/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Células T Auxiliares Foliculares/imunologia , Anticorpos Neutralizantes/imunologia , Reações Cruzadas , Humanos , Receptores CXCR3/imunologia
18.
FASEB J ; 35(1): e21228, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337555

RESUMO

Asthmatic airways feature increased ASM mass that is largely attributable to hyperplasia, and which potentially contributes to excessive airway narrowing. T cells induce ASMC proliferation via contact-dependent mechanisms in vitro that may have importance for asthmatic ASM growth, as CD4+ T cells infiltrate ASM bundles in asthmatic human airways. In this study, we used an in vitro migration assay to investigate the pathways responsible for the trafficking of human CD4+ T cells to ASM. ASMCs induced chemotaxis of activated CD4+ T cells, which was inhibited by the CXCR3 antagonist AMG487 and neutralizing antibodies against its ligands CXCL10 and 11, but not CCR3 or CCR5 antagonists. CXCR3 expression was upregulated among all T cells following anti-CD3/CD28-activation. CD4+ T cells upregulated CXCL9, 10, and 11 expression in ASMCs in an IFN-γ/STAT1-dependent manner. Disruption of IFN-γ-signaling resulted in reduced T cell migration, along with the inhibition of CD4+ T cell-mediated STAT1 activation and CXCR3 ligand secretion by ASMCs. ASMCs derived from healthy and asthmatic donors demonstrated similar T cell-recruiting capacities. In vivo CXCL10 and 11 expression by asthmatic ASM was confirmed by immunostaining. We conclude that the CXCL10/11-CXCR3 axis causes CD4+ T cell recruitment to ASM that is amplified by T cell-derived IFN-γ.


Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Músculo Liso/imunologia , Receptores CXCR3/imunologia , Acetamidas/farmacologia , Anticorpos Neutralizantes/farmacologia , Asma/patologia , Células Cultivadas , Quimiocina CXCL11/imunologia , Humanos , Músculo Liso/patologia , Pirimidinonas/farmacologia , Receptores CXCR3/antagonistas & inibidores
19.
J Immunother Cancer ; 8(2)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33229509

RESUMO

BACKGROUND: In 2016 the first-in-human phase I study of a miRNA-based cancer therapy with a liposomal mimic of microRNA-34a-5p (miR-34a-5p) was closed due to five immune related serious adverse events (SAEs) resulting in four patient deaths. For future applications of miRNA mimics in cancer therapy it is mandatory to unravel the miRNA effects both on the tumor tissue and on immune cells. Here, we set out to analyze the impact of miR-34a-5p over-expression on the CXCL10/CXCL11/CXCR3 axis, which is central for the development of an effective cancer control. METHODS: We performed a whole genome expression analysis of miR-34a-5p transfected M1 macrophages followed by an over-representation and a protein-protein network analysis. In-silico miRNA target prediction and dual luciferase assays were used for target identification and verification. Target genes involved in chemokine signaling were functionally analyzed in M1 macrophages, CD4+ and CD8+ T cells. RESULTS: A whole genome expression analysis of M1 macrophages with induced miR-34a-5p over-expression revealed an interaction network of downregulated target mRNAs including CXCL10 and CXCL11. In-silico target prediction in combination with dual luciferase assays identified direct binding of miR-34a-5p to the 3'UTRs of CXCL10 and CXCL11. Decreased CXCL10 and CXCL11 secretion was shown on the endogenous protein level and in the supernatant of miR-34a-5p transfected and activated M1 macrophages. To complete the analysis of the CXCL10/CXCL11/CXCR3 axis, we activated miR-34a-5p transfected CD4+ and CD8+ T cells by PMA/Ionomycin and found reduced levels of endogenous CXCR3 and CXCR3 on the cell surface. CONCLUSIONS: MiR-34a-5p mimic administered by intravenous administration will likely not only be up-taken by the tumor cells but also by the immune cells. Our results indicate that miR-34a-5p over-expression leads in M1 macrophages to a reduced secretion of CXCL10 and CXCL11 chemokines and in CD4+ and CD8+ T cells to a reduced expression of CXCR3. As a result, less immune cells will be attracted to the tumor site. Furthermore, high levels of miR-34a-5p in naive CD4+ T cells can in turn hinder Th1 cell polarization through the downregulation of CXCR3 leading to a less pronounced activation of cytotoxic T lymphocytes, natural killer, and natural killer T cells and possibly contributing to lymphocytopenia.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiocina CXCL10/imunologia , Quimiocina CXCL11/imunologia , Macrófagos/imunologia , MicroRNAs/metabolismo , Receptores CXCR3/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/genética , Quimiocina CXCL11/metabolismo , Células HEK293 , Humanos , RNA Mensageiro/genética , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Transdução de Sinais
20.
Int J Mol Sci ; 21(19)2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32977372

RESUMO

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-ß (TGF-ß) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.


Assuntos
Movimento Celular/imunologia , Membrana Basal Glomerular/imunologia , Glomerulonefrite Membranosa/imunologia , Fator 15 de Diferenciação de Crescimento/imunologia , Proteinúria/imunologia , Linfócitos T/imunologia , Animais , Movimento Celular/genética , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Membrana Basal Glomerular/patologia , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/patologia , Fator 15 de Diferenciação de Crescimento/genética , Camundongos , Camundongos Knockout , Proteinúria/genética , Proteinúria/patologia , Receptores CXCR3/genética , Receptores CXCR3/imunologia , Linfócitos T/patologia
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