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1.
Proc Natl Acad Sci U S A ; 120(1): e2210490120, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36574651

RESUMO

γδ T cells are involved in the control of Staphylococcus aureus infection, but their importance in protection compared to other T cells is unclear. We used a mouse model of systemic S. aureus infection associated with high bacterial load and persistence in the kidney. Infection caused fulminant accumulation of γδ T cells in the kidney. Renal γδ T cells acquired tissue residency and were maintained in high numbers during chronic infection. At day 7, up to 50% of renal γδ T cells produced IL-17A in situ and a large fraction of renal γδ T cells remained IL-17A+ during chronic infection. Controlled depletion revealed that γδ T cells restricted renal S. aureus replication in the acute infection and provided protection during chronic renal infection and upon reinfection. Our results demonstrate that kidney-resident γδ T cells are nonredundant in limiting local S. aureus growth during chronic infection and provide enhanced protection against reinfection.


Assuntos
Interleucina-17 , Infecções Estafilocócicas , Camundongos , Animais , Staphylococcus aureus , Receptores de Antígenos de Linfócitos T gama-delta , Infecção Persistente , Reinfecção , Rim , Camundongos Endogâmicos C57BL
2.
PLoS Pathog ; 18(4): e1010430, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35446923

RESUMO

Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.


Assuntos
Sepse , Infecções Estafilocócicas , Proteínas com Domínio T/metabolismo , Animais , Plasticidade Celular , Humanos , Interleucina-17 , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Staphylococcus aureus , Células Th1 , Células Th17
3.
Sci Immunol ; 9(96): eadd6774, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875317

RESUMO

Pro-inflammatory CD4+ T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (TH17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in TH17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (TH1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover TH17 to TH1 cell plasticity in the human kidney in the context of renal autoimmunity.


Assuntos
Análise de Célula Única , Células Th17 , Animais , Humanos , Camundongos , Células Th17/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/genética , Plasticidade Celular/imunologia , Plasticidade Celular/genética , Rim/imunologia , Rim/patologia , Camundongos Endogâmicos C57BL , Sistemas CRISPR-Cas , Colite/imunologia , Colite/genética , Inflamação/imunologia , Inflamação/genética , Feminino , Masculino , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/imunologia
4.
Sci Transl Med ; 15(687): eadd6137, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36921033

RESUMO

GM-CSF in glomerulonephritisDespite glomerulonephritis being an immune-mediated disease, the contributions of individual immune cell types are not clear. To address this gap in knowledge, Paust et al. characterized pathological immune cells in samples from patients with glomerulonephritis and in samples from mice with the disease. The authors found that CD4+ T cells producing granulocyte-macrophage colony-stimulating factor (GM-CSF) licensed monocytes to promote disease by producing matrix metalloproteinase 12 and disrupting the glomerular basement membrane. Targeting GM-CSF to inhibit this axis reduced disease severity in mice, implicating this cytokine as a potential therapeutic target for patients with glomerulonephritis. -CM.


Assuntos
Glomerulonefrite , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Camundongos , Animais , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Monócitos/metabolismo , Metaloproteinase 12 da Matriz/metabolismo , Linfócitos T CD4-Positivos , Glomerulonefrite/metabolismo
5.
Sci Immunol ; 6(56)2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33622974

RESUMO

Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of IL17A and CSF2 (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.


Assuntos
COVID-19/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Memória Imunológica , Pulmão/imunologia , Células Th17/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/complicações , COVID-19/patologia , Células Clonais , Humanos , Inflamação/etiologia , Inflamação/imunologia , Pulmão/patologia , Células Mieloides , Pneumonia Bacteriana/imunologia , Células Th17/imunologia
6.
Sci Immunol ; 5(50)2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769171

RESUMO

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (TRM) cells persist in peripheral organs and provide immune protection against reinfection. However, whether TRM cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4+ TRM cells with a TH17 signature (termed TRM17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal TRM17 cells were induced by pathogens infecting the kidney, such as Staphylococcus aureus, Candida albicans, and uropathogenic Escherichia coli, and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney TRM17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced TRM17 cells have a previously unrecognized function in aggravating autoimmune disease.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Infecções Bacterianas/imunologia , Linfócitos T CD4-Positivos/imunologia , Candidíase/imunologia , Glomerulonefrite/imunologia , Rim/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/microbiologia , Candida albicans , Glomerulonefrite/microbiologia , Humanos , Memória Imunológica , Masculino , Camundongos Endogâmicos DBA , Camundongos Transgênicos
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