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γδ T cells are involved in the control of

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.

Tissue-resident memory-like TH17 cells are clonally expanded in bronchoalveolar lavage fluid of patients with severe COVID-19., TH17 cells in severe COVID-19 Generation of T helper 17 (TH17) cells has been associated with immunopathogenesis in multiple autoimmune diseases. Using integrated single-cell transcriptome and TCR repertoire profiling, Zhao et al. showed that a population of TH17 cells with features of tissue-resident memory T cells was clonally expanded in bronchoalveolar lavage (BAL) fluid collected from the lungs of patients with severe COVID-19, but not in samples from patients with bacterial pneumonia. Lung tissue–resident memory-like TH17 cells were the primary immune cell type in BAL expressing the cytokine GM-CSF, which was also elevated in serum from a cohort of patients with severe COVID-19 compared with those with moderate disease. These results provide insight into specific T cell responses associated with severe COVID-19 pneumonia and identify a potential cellular target of GM-CSF–neutralizing therapies., Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome 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 patients with severe COVID-19 and patients with bacterial pneumonia 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 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 patients with COVID-19 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.

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.

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (T

Summary Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell “reservoir” may present a therapeutic strategy for these autoimmune disorders., Graphical Abstract, Highlights • Pathogenic TH17 cells migrate from the gut to the kidney in autoimmunity • TH17 cells egress the intestine in a S1PR1-dependent manner in glomerulonephritis • Targeting microbiota-induced TH17 cells ameliorates extraintestinal TH17 responses, By photolabelling intestinal cells, Krebs and colleagues provide direct evidence that microbiota-induced TH17 cells egress from the gut S1PR1-dependently and infiltrate the kidney via CCL20/CCR6 in immune-mediated diseases. This finding will build the basis for therapies targeting the intestinal TH17 cell “reservoir” to treat extraintestinal TH17 autoimmunity.

Background: To diagnose Pneumocystis jirovecii pneumonia (PCP), PCR testing in bronchoalveolar lavage (BAL) fluid has recently become an alternative to immunofluorescence testing (IFT); however, its diagnostic accuracy is less clear. Objective: To analyze the diagnostic value of a new semiquantitative real-time PCR (RT-PCR) in BAL in a real-life clinical setting. Methods: Retrospective analysis of all RT-PCR results [semiquantitative: negative, weakly positive, and strongly positive; measured in cycle thresholds (Ct)] in BAL in the period between 2010 and 2014. The diagnosis of PCP was defined by clinical, radiological, and laboratory signs and by treatment initiation. Any positive PCR was compared with subsequent IFT. Results: Of 128 patient samples, 32 had PCP. There is a relevant correlation of high significance between positive PCR Ct and IFT (r = -0.7781, p < 0.001), which amounts to about 60% of the variance. Sensitivity, specificity, and positive predictive values (PPV) of any positive RT-PCR were 100, 80, and 63%, respectively. No patient with negative RT-PCR had PCP. Specificity and PPV are 100% in strongly positive RT-PCR, whereas they decrease to 80 and 21% in weakly positive RT-PCR. Conclusion: A negative RT-PCR (Ct >45) rules out PCP. A strongly positive PCR (Ct

Background: To diagnose Pneumocystis-Pneumonia (PCP), PCR testing of P. jirovecii (PJ) in bronchoalveolar lavage (BAL) fluid has recently become an alternative to immunofluorescence testing (IFT), however its significance is less clear. Aim: To analyse the value of semi-quantitative real time PCR in BAL in diagnosing PCP. Methods: Retrospective analysis of all PJ-PCR results (semi-quantitative: negative, weak positive, high positive) in BAL from 2010 to 2014 in a respiratory and infectious diseases centre. Any positive PCR was compared with subsequent IFT; negative results were not compared. Diagnosis of PCP was defined by clinical, radiological and laboratory signs and by treatment response. Results: 128 patient samples (mean age 51 years, 59,2% male, 27,6% HIV positive), of which 32 had PCP. Negative PCR (n=76): 0 (0%) had PCP, IFT was not performed. Weak positive PCR (n=24): 4 (16,7%) had PCP, IFT was positive in 0 (0%). High positive PCR (n=28): 28 (100%) had PCP, IFT was positive in 23 (82,1%). Strong correlation of high significance between PCR (cycle threshold) and IFT (r=-0,7781, p