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1.
J Neuroinflammation ; 21(1): 43, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38317227

RESUMO

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.


Assuntos
Glaucoma , Células Ganglionares da Retina , Humanos , Camundongos , Animais , Células Ganglionares da Retina/patologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Células Th1/patologia , Glaucoma/metabolismo , Retina/patologia , Transtornos da Visão/patologia , Modelos Animais de Doenças
2.
J Pediatr Gastroenterol Nutr ; 78(2): 231-240, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38374564

RESUMO

OBJECTIVES: Collagenous gastritis (CG) is a rare cause of refractory dyspepsia and anemia that frequently affects children and young adults and whose histological hallmark is chronic mucosal inflammation with a subepithelial collagen band. The etiology remains obscure, and no established treatments exist. We investigated the pathogenesis of CG by determining the expression profiles of genes related to immunity and inflammation in index biopsies. METHODS: Gastric biopsies from 10 newly diagnosed patients with CG were evaluated using the NanoString nCounter assay. Gastric biopsies from 14 normal individuals served as controls. The gene expression ratios for CG versus controls were determined in pooled samples and confirmed in individual samples by quantitative reverse transcription polymerase chain reaction. The results were compared with previously reported expression data from a cohort of patients with collagenous colitis, a colonic disorder with similar morphology, including subepithelial collagen band. RESULTS: CG biopsies featured enhanced expression of key genes encoding both Th1 (IFNγ, TNF-α, IL-2, IL-10, IL-12A, IL-12B, and IL-18) and Th2 cytokines (IL-3, IL-4, IL-5, IL-6, and IL-13). In contrast, biopsies from patients with CC exhibited upregulated Th1 cytokines only. CONCLUSIONS: We show in this first published gene expression profiling study that CG involves simultaneous upregulation of Th1 and Th2 cytokines. This finding is unique, contrasting with other types of chronic gastritis as well as with collagenous colitis, which shares the presence of a collagen band. Involvement of Th2 immunity in CG would support further investigation of potential dietary, environmental, or allergic factors to guide future therapeutic trials.


Assuntos
Colite Colagenosa , Gastrite , Síndromes de Malabsorção , Criança , Adulto Jovem , Humanos , Colite Colagenosa/genética , Citocinas , Gastrite/diagnóstico , Inflamação/complicações , Colágeno/análise , Síndromes de Malabsorção/complicações , Células Th1/metabolismo , Células Th1/patologia
3.
Nature ; 626(7997): 160-168, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38233524

RESUMO

Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.


Assuntos
Autoimunidade , Linfócitos T CD8-Positivos , Síndrome de Guillain-Barré , Nervos Periféricos , Doenças do Sistema Nervoso Periférico , Células Th1 , Humanos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Síndrome de Guillain-Barré/sangue , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/etiologia , Síndrome de Guillain-Barré/imunologia , Antígenos HLA-DR/imunologia , Epitopos Imunodominantes/imunologia , Bainha de Mielina/imunologia , Nervos Periféricos/imunologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Células Th1/imunologia , Células Th1/patologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Memória Imunológica
4.
Int Immunopharmacol ; 129: 111594, 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38295547

RESUMO

BACKGROUND: Cathepsins have been recently identified as a regulator in the activation of Th1 and Th17 cells, which play an important role in the pathogenesis of anti-glomerular basement membrane (GBM) disease. Whether cathepsins contribute to the development of anti-GBM disease through regulating the activation of CD4+ T cell is still unclear. METHODS: Rats with experimental anti-GBM disease was established by immunization with the nephritogenic T cell epitope α3127-148. E64d, a cysteine cathepsin inhibitor, was administered in vitro and vivo to evaluate the effect of cathepsins on regulating the activation of antigen specific T cells and the development of anti-GBM disease. RESULTS: In rats with experimental anti-GBM diseases, E64d treatment not only reduced the levels of proteinuria, serum creatinine and anti-GBM antibody, but also ameliorated the kidney injury with less glomerular IgG deposition, a lower percentage of crescents and less infiltration of CD4+ T cells, CD8+ T cells and macrophages, as well as a lower percentage of splenic Th1 cells. In vitro, E64d treatment could significantly reduce the production of IFN-γ in the supernatant which might be produced by the activation of Th1 cells after being recalled with the autoantigen α3127-148. We also found the CD4+ T cells of rats with anti-GBM disease had an increased expression of cathepsin L (Cts-L), and the percentage of CD4+ T cells with extracellular expression of Cts-L was obviously higher, indicating it as a potential key regulator. CONCLUSIONS: E64d might attenuate the development of anti-GBM disease by participating in the activation of Th1 cells, indicating it as a potential drug for anti-GBM disease in the future.


Assuntos
Doença Antimembrana Basal Glomerular , Leucina/análogos & derivados , Ratos , Animais , Doença Antimembrana Basal Glomerular/tratamento farmacológico , Doença Antimembrana Basal Glomerular/patologia , Células Th1/patologia , Linfócitos T CD8-Positivos , Autoantígenos , Catepsinas , Membrana Basal/patologia
5.
Neurosci Bull ; 40(1): 17-34, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37498431

RESUMO

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4+ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4+ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Humanos , Camundongos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Encefalomielite Autoimune Experimental/metabolismo , Camundongos Endogâmicos C57BL , Células Th1/metabolismo , Células Th1/patologia
6.
Nat Med ; 29(10): 2602-2614, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37749331

RESUMO

Aberrant CD4+ T cell reactivity against intestinal microorganisms is considered to drive mucosal inflammation in inflammatory bowel diseases. The disease-relevant microbial species and the corresponding microorganism-specific, pathogenic T cell phenotypes remain largely unknown. In the present study, we identified common gut commensal and food-derived yeasts, as direct activators of altered CD4+ T cell reactions in patients with Crohn's disease (CD). Yeast-responsive CD4+ T cells in CD display a cytotoxic T helper cell (TH1 cell) phenotype and show selective expansion of T cell clones that are highly cross-reactive to several commensal, as well as food-derived, fungal species. This indicates cross-reactive T cell selection by repeated encounter with conserved fungal antigens in the context of chronic intestinal disease. Our results highlighted a role of yeasts as drivers of aberrant CD4+ T cell reactivity in patients with CD and suggest that both gut-resident fungal commensals and daily dietary intake of yeasts might contribute to chronic activation of inflammatory CD4+ T cell responses in patients with CD.


Assuntos
Doença de Crohn , Doenças Inflamatórias Intestinais , Humanos , Doença de Crohn/microbiologia , Linfócitos T CD4-Positivos , Doenças Inflamatórias Intestinais/patologia , Linfócitos T Auxiliares-Indutores , Células Clonais/patologia , Mucosa Intestinal/patologia , Células Th17/patologia , Células Th1/patologia
7.
Jpn J Infect Dis ; 76(3): 183-190, 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-36724936

RESUMO

The development of a vaccine against human respiratory syncytial virus (HRSV) has been hampered by enhanced respiratory disease due to the Th2-biased immune response. In the present study, MA103 and aluminum phosphate (Adju-Phos) adjuvants were used to verify the immunogenicity of the recombinant fusion (RBF) protein (F protein expressed by Escherichia coli). Both adjuvants significantly increased the neutralizing antibody titer and number of interferon gamma (IFN-γ)-secreting CD4+ T cells in mice. Based on the immunoglobulin G1 (IgG1)/IgG2a and IFN-γ/interleukin 4-secreting CD4+ T cell ratio, however, MA103 significantly enhanced the Th1-biased immune response. The pathological damage to the lung in the RBF/MA103 group was less than what was seen in the RBF/Adju-Phos group. Additionally, the number of HRSV copies in the lungs of the RBF/MA103 group decreased by approximately 3 × log10. These results suggested that MA103 provides better protection against HRSV in mice.


Assuntos
Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Camundongos , Humanos , Animais , Vírus Sincicial Respiratório Humano/genética , Proteínas Recombinantes de Fusão , Células Th1/metabolismo , Células Th1/patologia , Camundongos Endogâmicos BALB C , Anticorpos Antivirais , Adjuvantes Imunológicos , Proteínas Recombinantes , Interferon gama
8.
Haematologica ; 108(4): 1068-1082, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35833296

RESUMO

Classical Hodgkin lymphoma (CHL) is unusually sensitive to PD1 inhibition and PDL1 is highly expressed on CHL cells and in the tumor microenvironment. This could be interpreted as evidence of exhaustion, but paradoxically, PD1+ lymphocyte infiltration does not predict response to PD1 inhibitors and no increase in cytotoxic markers is seen after PD1 therapy as might be expected with reversal of exhaustion. In contrast to PD1, elevated PDL1 does predict response to PD1 inhibitors and recent data associate both retained CHL MHC-II expression and increased T helper (TH) T-cell receptor diversity with response, suggesting a connection to the TH compartment. We performed a phenotypic, spatial and functional assessment of T-cell exhaustion in CHL and found co-expression of an exhaustion marker and lower PD1 expression in CHL than in reactive nodes whereas the proliferative and cytokine production capacity were similar in CHL and the reactive nodes. We found no correlation between PDL1 expression and exhaustion signatures. Instead, we identified a strong association between PDL1 expression and CHL MHC-II expression, TH recruitment, and enrichment of TH1 regulatory cells. These data suggest that a dominant effect of PDL1 expression in CHL may be TH engagement and promotion of a regulatory microenvironment rather than maintenance of exhaustion.


Assuntos
Doença de Hodgkin , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Doença de Hodgkin/patologia , Exaustão das Células T , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th1/patologia , Microambiente Tumoral
9.
J Neuroimmune Pharmacol ; 17(3-4): 409-422, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36443518

RESUMO

Upon different stimulation, naïve CD4+ T cells differentiate into various subsets of T helper (Th) cells, including Th1, Th2, Th17, and Tregs. They play both protective and pathogenic roles in the central nervous system (CNS) by secreting different cytokines. Failure of the homeostasis of the subgroups in the CNS can result in different brain diseases. Recently, immunotherapy has drawn more and more attention in the therapy of various brain diseases. Here, we describe the role of different CD4+ T cell subsets and their secreted cytokines in various brain diseases, as well as the ways in which by affecting CD4+ T cells in therapy of the CNS diseases. Understanding the role of CD4+ T cells and their secreted cytokines in the immunotherapy of brain disease will provide new targets and therapeutics for the treatment of brain disease. The role of CD4 + T cell subtypes in different diseases and their associated regulatory genes, proteins, and enzymes. CD4 + T cell subtypes play both protective (green) and pathogenic (red) roles in different brain diseases. The immune regulatory effects of CD4 + T cells and their subtypes are promoted or inhibited by different genes, proteins, and enzymes.


Assuntos
Encefalopatias , Citocinas , Humanos , Citocinas/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Th17/metabolismo , Encefalopatias/terapia , Encefalopatias/metabolismo , Encefalopatias/patologia , Imunoterapia , Células Th1/metabolismo , Células Th1/patologia
10.
PLoS Biol ; 20(8): e3001554, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-36026478

RESUMO

Multiple sclerosis (MS) is a highly prevalent demyelinating autoimmune condition; the mechanisms regulating its severity and progression are unclear. The IL-17-producing Th17 subset of T cells has been widely implicated in MS and in the mouse model, experimental autoimmune encephalomyelitis (EAE). However, the differentiation and regulation of Th17 cells during EAE remain incompletely understood. Although evidence is mounting that the antimicrobial peptide cathelicidin profoundly affects early T cell differentiation, no studies have looked at its role in longer-term T cell responses. Now, we report that cathelicidin drives severe EAE disease. It is released from neutrophils, microglia, and endothelial cells throughout disease; its interaction with T cells potentiates Th17 differentiation in lymph nodes and Th17 to exTh17 plasticity and IFN-γ production in the spinal cord. As a consequence, mice lacking cathelicidin are protected from severe EAE. In addition, we show that cathelicidin is produced by the same cell types in the active brain lesions in human MS disease. We propose that cathelicidin exposure results in highly activated, cytokine-producing T cells, which drive autoimmunity; this is a mechanism through which neutrophils amplify inflammation in the central nervous system.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Peptídeos Catiônicos Antimicrobianos , Peptídeos Antimicrobianos , Diferenciação Celular , Encefalomielite Autoimune Experimental/patologia , Células Endoteliais/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/metabolismo , Células Th1/patologia , Células Th17/metabolismo , Catelicidinas
11.
Redox Biol ; 56: 102454, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36044789

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor. Although numerous postoperative therapeutic strategies have already been developed, including radiotherapy, tumors inevitably recur after several years of treatment. The coinhibitory molecule B7-H4 negatively regulates T cell immune responses and promotes immune escape. Exosomes mediate intercellular communication and initiate immune evasion in the tumor microenvironment (TME). OBJECTIVE: This study aimed to determine whether B7-H4 is upregulated by radiation and loaded into exosomes, thus contributing to immunosuppression and enhancing tumor growth. METHODS: Iodixanol density-gradient centrifugation and flow cytometry were used to verify exosomal B7-H4. Naïve T cells were differentiated into Th1 cells, with or without exosomes. T cell-secreted cytokines and markers of T cell subsets were measured. Mechanistically, the roles of B7-H4, and ALIX in GBM were analyzed using databases and tissue samples. Co-immunoprecipitation, and pull-down assays were used to tested the direct interactions between ATM and ALIX or STAT3. In vitro ATM kinase assays, western blotting, and site-directed mutation were used to assess ATM-mediated STAT3 phosphorylation. Finally, the contribution of exosomal B7-H4 to immunosuppression and tumor growth was investigated in vivo. RESULTS: Exosomes from irradiated GBM cells decreased the anti-tumor immune response of T cell in vitro and in vivo via delivered B7-H4. Mechanistically, irradiation promoted exosome biogenesis by increasing the ATM-ALIX interaction. Furthermore, the ATM-phosphorylated STAT3 was found to directly binds to the B7-H4 promoter to increase its expression. Finally, the radiation-induced increase in exosomal B7-H4 induced FoxP3 expression during Th1 cell differentiation via the activated STAT1 pathway. In vivo, exosomal B7-H4 decreased the radiation sensitivity of GBM cells, and reduced the survival of GBM mice model. CONCLUSION: This study showed that radiation-enhanced exosomal B7-H4 promoted immunosuppression and tumor growth, hence defining a direct link between irradiation and anti-tumor immune responses. Our results suggest that co-administration of radiotherapy with anti-B7-H4 therapy could improve local tumor control and identify exosomal B7-H4 as a potential tumor biomarker.


Assuntos
Glioblastoma , Neuroblastoma , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Citocinas , Fatores de Transcrição Forkhead/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/radioterapia , Camundongos , Células Th1/metabolismo , Células Th1/patologia , Microambiente Tumoral , Inibidor 1 da Ativação de Células T com Domínio V-Set/genética , Inibidor 1 da Ativação de Células T com Domínio V-Set/metabolismo
12.
Pharmacol Biochem Behav ; 217: 173408, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35644272

RESUMO

Autism spectrum disorders is a complex neurodevelopmental disorder characterized by abnormal social interaction, defective communication, repetitive and stereotyped patterns of behaviors or interests. The BTBR T+ Itpr3tf/J (BTBR) inbred mice are generally used as a model for ASD, display a range of autistic phenotypes. Recent studies suggest that the CXCR2 antagonist is crucial for targets in the treatment of inflammatory and neurodegenerative diseases. In this study, we investigated the potential effects of the CXCR2 antagonist SB332235 on sociability behaviors, marble burying, and self-grooming, we also explored the treatment of SB332235 on Th1 (IFN-γ, Stat1, and T-bet), Th22 (IL-22, TNF-α, and AhR), and T regulatory (Treg, IL-10, Helios and Foxp3) production in CD4+ T cells in male BTBR and C57BL/6 (C57) mice in spleen. We also investigated the effects of SB332235 on IFN-γ, IL-10, IL-22, T-bet, AhR, and Foxp3 mRNA expression levels in the brain tissues. The SB332235-treated mice significantly improve behavioral abnormalities in BTBR mice. In addition, SB332235 administration causes a significantly decreases in IFN-γ, Stat1, T-bet, IL-22, TNF-α, and AhR, and increases in IL-10, Foxp3 and Helios production CD4+ T cells in BTBR mice. We further observed that SB332235 downregulated IFN-γ, IL-10, IL-22, T-bet, and AhR, and upregulated IL-10 and Foxp3 mRNA expression in the brain tissues. Our findings demonstrated that SB332235 treatment attenuated behavior deficits, through inhibiting Th1/Th22 and upregulating Treg cell-related transcription factors signaling pathway. Therefore, CXCR2 antagonist administration may be a promising therapeutic agent to attenuate behavior deficits via its anti-inflammatory effect.


Assuntos
Transtorno Autístico , Receptores de Interleucina-8B , Comportamento Social , Sulfonamidas , Linfócitos T Reguladores , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , RNA Mensageiro/metabolismo , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th1/patologia
13.
J Clin Invest ; 132(12)2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35503257

RESUMO

Antigen-presenting cells (APCs) integrate signals emanating from local pathology and program appropriate T cell responses. In allogeneic hematopoietic stem cell transplantation (alloHCT), recipient conditioning releases damage-associated molecular patterns (DAMPs) that generate proinflammatory APCs that secrete IL-12, which is a driver of donor Th1 responses, causing graft-versus-host disease (GVHD). Nevertheless, other mechanisms exist to initiate alloreactive T cell responses, as recipients with disrupted DAMP signaling or lacking IL-12 develop GVHD. We established that tissue damage signals are perceived directly by donor CD4+ T cells and promoted T cell expansion and differentiation. Specifically, the fibroblastic reticular cell-derived DAMP IL-33 is increased by recipient conditioning and is critical for the initial activation, proliferation, and differentiation of alloreactive Th1 cells. IL-33 stimulation of CD4+ T cells was not required for lymphopenia-induced expansion, however. IL-33 promoted IL-12-independent expression of Tbet and generation of Th1 cells that infiltrated GVHD target tissues. Mechanistically, IL-33 augmented CD4+ T cell TCR-associated signaling pathways in response to alloantigen. This enhanced T cell expansion and Th1 polarization, but inhibited the expression of regulatory molecules such as IL-10 and Foxp3. These data establish an unappreciated role for IL-33 as a costimulatory signal for donor Th1 generation after alloHCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Interleucina-12 , Interleucina-33/genética , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/patologia
14.
J Clin Invest ; 132(12)2022 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-35503658

RESUMO

Bone metastases are frequent complications of malignant melanoma leading to reduced quality of life and significant morbidity. Regulation of immune cells by the gut microbiome influences cancer progression, but the role of the microbiome in tumor growth in bone is unknown. Using intracardiac or intratibial injections of B16-F10 melanoma cells into mice, we showed that gut microbiome depletion by broad-spectrum antibiotics accelerated intraosseous tumor growth and osteolysis. Microbiome depletion blunted melanoma-induced expansion of intestinal NK cells and Th1 cells and their migration from the gut to tumor-bearing bones. Demonstrating the functional relevance of immune cell trafficking from the gut to the bone marrow (BM) in bone metastasis, blockade of S1P-mediated intestinal egress of NK and Th1 cells, or inhibition of their CXCR3/CXCL9-mediated influx into the BM, prevented the expansion of BM NK and Th1 cells and accelerated tumor growth and osteolysis. Using a mouse model, this study revealed mechanisms of microbiota-mediated gut-bone crosstalk that are relevant to the immunological restraint of melanoma metastasis and tumor growth in bone. Microbiome modifications induced by antibiotics might have negative clinical consequences in patients with melanoma.


Assuntos
Microbioma Gastrointestinal , Melanoma Experimental , Osteólise , Animais , Antibacterianos/farmacologia , Desenvolvimento Ósseo , Humanos , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Qualidade de Vida , Células Th1/patologia
15.
Am J Nephrol ; 53(5): 388-396, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35413717

RESUMO

INTRODUCTION: Thy1.1 glomerulonephritis (Thy1.1 GN) in rats is widely used as an experimental model of mesangial proliferative glomerulonephritis (GN). We previously reported that T-helper (Th) cells were accumulated in glomeruli from the early phase of this model and that not Th2 cells but Th1 cells play an important role in the development of glomerular alterations. Although Th17 is reported to be involved in the pathogenesis of several autoimmune diseases, the role of Th17 cells in the pathogenesis of mesangial alterations in Thy1.1 GN remains unclear. METHODS: The kinetics of the infiltration of subsets of Th cells and the expression of IL-17 in Thy1.1 GN were analyzed. Next, the localization and the cell types of IL-17 receptor (IL-17R)-positive cells and IL-6-positive cells were analyzed. Then, the effect of tacrolimus on the expressions of Th17-related cytokines in Thy1.1 GN was analyzed. RESULTS: Not only Th1 cells but also Th17 cells were recruited into glomeruli from the early phase of the disease. mRNA expression of IL-17 in glomeruli was elevated. The increased positive expression of IL-17R was detected in the mesangial area, and some of IL-17R-positive cells were co-stained with IL-6. Tacrolimus treatment ameliorated mesangial alterations by suppressing the expressions of Th17-related cytokines such as IL-17 and IL-6. CONCLUSION: Th17 cells participate in the development of Thy1.1 GN, a mimic of mesangial proliferative GN, and Th17 cells and their related cytokines are pertinent therapeutic targets.


Assuntos
Glomerulonefrite , Tacrolimo , Animais , Citocinas/metabolismo , Glomerulonefrite/tratamento farmacológico , Humanos , Interleucina-17 , Interleucina-6 , Ratos , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Células Th1/metabolismo , Células Th1/patologia , Células Th17/metabolismo , Células Th17/patologia , Antígenos Thy-1
16.
PLoS One ; 17(3): e0264400, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35263357

RESUMO

The health and economic burden of colitis is increasing globally. Understanding the role of host genetics and metagenomics is essential to establish the molecular basis of colitis pathogenesis. In the present study, we have used a common composite dose of DSS to compare the differential disease severity response in C57BL/6 (Th1 biased) and BALB/c (Th2 biased) mice with zero mortality rates. We employed multi-omics approaches and developed a newer vector analysis approach to understand the molecular basis of the disease pathogenesis. In the current report, comparative transcriptomics, metabonomics, and metagenomics analyses revealed that the Th1 background of C57BL/6 induced intense inflammatory responses throughout the treatment period. On the contrary, the Th2 background of BALB/c resisted severe inflammatory responses by modulating the host's inflammatory, metabolic, and gut microbial profile. The multi-omics approach also helped us discover some unique metabolic and microbial markers associated with the disease severity. These biomarkers could be used in diagnostics.


Assuntos
Colite , Células Th1 , Animais , Colite/induzido quimicamente , Colite/genética , Colite/patologia , Metagenômica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células Th1/patologia , Células Th2/patologia
17.
Clin Transl Med ; 12(3): e771, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35343079

RESUMO

G protein-coupled receptor 65 (GPR65), a susceptibility gene for inflammatory bowel diseases (IBD), has been identified to promote Th17 cell pathogenicity and induce T cell apoptosis. However, the potential role of GPR65 in modulating CD4+ T cell immune responses in the pathogenesis of IBD stills not entirely understood. Here, we displayed that GPR65 expression was increased in inflamed intestinal mucosa of IBD patients and positively associated with disease activity. It was expressed in CD4+ T cells and robustly upregulated through the TNF-α-caspase 3/8 signalling pathway. Ectopic expression of GPR65 significantly promoted the differentiation of peripheral blood (PB) CD4+ T cells from IBD patients and HC to Th1 and Th17 cells in vitro. Importantly, conditional knockout of Gpr65 in CD4+ T cells ameliorated trinitrobenzene sulfonic acid (TNBS)-induced acute murine colitis and a chronic colitis in Rag1-/- mice reconstituted with CD45RBhigh CD4+ T cells in vivo, characterised by attenuated Th1 and Th17 cell immune response in colon mucosa and decreased infiltration of CD4+ T cells, neutrophils and macrophages. RNA-seq analysis of Gpr65ΔCD4 and Gpr65flx/flx CD4+ T cells revealed that NUAK family kinase 2 (Nuak2) acts as a functional target of Gpr65 to restrict Th1 and Th17 cell immune response. Mechanistically, GPR65 deficiency promoted NUAK2 expression via the cAMP-PKA-C-Raf-ERK1/2-LKB1-mediated signalling pathway. Consistently, silencing of Nuak2 facilitated the differentiation of Gpr65ΔCD4 and Gpr65flx/flx CD4+ T cells into Th1 and Th17 cells. Therefore, our data point out that GPR65 promotes Th1 and Th17 cell immune response and intestinal mucosal inflammation by suppressing NUAK2 expression, and that targeting GPR65 and NUAK2 in CD4+ T cells may represent a novel therapeutic approach for IBD.


Assuntos
Células Th1 , Células Th17 , Animais , Diferenciação Celular/genética , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Proteínas Serina-Treonina Quinases , Receptores Acoplados a Proteínas G , Células Th1/patologia , Células Th17/patologia
18.
Immunol Med ; 45(2): 119-127, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35130134

RESUMO

Th17 cells are implicated in the pathogenesis of several autoimmune diseases. During the inflammation, Th17 cells exposed to IL-12 can shift towards the Th1 phenotype. These shifted cells are defined as 'non-classic Th1 cells'. Th17-derived non-classic Th1 cells play a critical role in late-onset chronic inflammatory diseases and are more pathogenic than the unshifted Th17 cells. Eomes is a transcription factor highly expressed in non-classic Th1 cells. To study the functional role of Eomes without genetic alteration, novel recombinant protein, ntEomes-TMD, was generated by fusing TMD of Eomes and Hph-1-PTD that facilitate intracellular delivery of its cargo molecule. ntEomes-TMD was delivered into the nucleus of the cells without influencing the T cell activation and cytotoxicity. ntEomes-TMD specifically inhibited the Eomes- and ROR-γt-mediated transcription and suppressed the Th1 and Th17 differentiation. Interestingly, ntEomes-TMD blocked the generation of non-classic Th1 cells from Th17 cells, leading to the inhibition of IFN-γ and GM-CSF secretion. In EAE, ntEomes-TMD alleviated the symptoms of EAE, and the combination treatment using ntEomes-TMD and anti-IL-17 mAb together showed better therapeutic efficacy than anti-IL-17 mAb treatment. The results suggest that ntEomes-TMD can be a new therapeutic reagent for treating chronic inflammatory diseases associated with non-classic Th1 cells.


Assuntos
Encefalomielite Autoimune Experimental , Células Th17 , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Inflamação , Células Th1/metabolismo , Células Th1/patologia , Células Th17/metabolismo , Células Th17/patologia
19.
Cell Cycle ; 21(9): 921-933, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35220890

RESUMO

Graves' disease (GD) is a kind of autoimmune diseases. The development of GD is closely related to the imbalance of Th1/Th2 generated by the differentiation of CD4+ T cells. This study was sought to clarify the role of lncRNA RUNX1-IT1 and explore the mechanism of its function. The expressions of RUNX1-IT1 and Neural cell adhesion molecule (NrCAM) in the peripheral blood of GD patients were detected by qRT-PCR and Western blot. We performed RNA pull down, RIP, and ChIP experiments to verify the correlation between p53 and RUNX1-IT1, p53 and NrCAM. The levels of Th1 cells differentiation markers were detected by Flow cytometry assay and ELISA. The expressions of lncRNA RUNX1-IT1 and NrCAM were most significantly up-regulated in CD4+ T cells of GD patients, and NrCAM expression was significantly positively correlated with RUNX1-IT1 expression. Furthermore, p53 was a potential transcription factor of NrCAM, which could interact with NrCAM. NrCAM level was up-regulated after the overexpression of p53 in CD4+ T cells, while knockdown of RUNX1-IT1 reversed this effect. Down-regulation of NrCAM and RUNX1-IT1 could decrease the mRNA and protein levels of transcriptional regulator T-bet and CXC chemokine ligand 10 (CXCL10) in CD4+ T cells. Our results suggested that RUNX1-IT1 regulated the expressions of the important Th1 factor T-bet, CXCL10, and interferon γ (IFN-γ) by regulating NrCAM transcription, thus participating in the occurrence and development of specific autoimmune disease GD.


Assuntos
Moléculas de Adesão Celular , Doença de Graves , RNA Longo não Codificante , Células Th1 , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Quimiocinas CXC/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Doença de Graves/genética , Doença de Graves/imunologia , Doença de Graves/metabolismo , Doença de Graves/patologia , Humanos , Moléculas de Adesão de Célula Nervosa/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Células Th1/imunologia , Células Th1/patologia , Células Th2/imunologia , Células Th2/patologia , Transcrição Gênica , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
20.
FEBS Lett ; 596(4): 427-436, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34939667

RESUMO

T helper cells, especially Th1 and Th17 cells, were reported to play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). However, the underlying factors regulating T cell functions in IBD progression remain to be fully elucidated. Here, we revealed that IL-17RD/Sef exacerbates DSS-induced colitis by regulating the balance of T cell subsets and their secretion of associated cytokines. We also observed that IL-17RD/Sef promotes colitis-associated tumorigenesis and negatively correlates with survival in both mouse and colorectal cancer patients. Our results suggested that IL-17RD/Sef functions as a regulator of T cell subsets to promote the inflammatory responses in the pathogenesis of IBD and colitis-associated colon cancer.


Assuntos
Carcinogênese/imunologia , Colite/imunologia , Proteínas de Membrana/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , Colite/induzido quimicamente , Colite/genética , Colite/mortalidade , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Contagem de Linfócitos , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Análise de Sobrevida , Células Th1/patologia , Células Th17/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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