A fundamental problem in biomedical research is the low number of observations available, mostly due to a lack of available biosamples, prohibitive costs, or ethical reasons. Augmenting few real ...observations with generated in silico samples could lead to more robust analysis results and a higher reproducibility rate. Here, we propose the use of conditional single-cell generative adversarial neural networks (cscGAN) for the realistic generation of single-cell RNA-seq data. cscGAN learns non-linear gene-gene dependencies from complex, multiple cell type samples and uses this information to generate realistic cells of defined types. Augmenting sparse cell populations with cscGAN generated cells improves downstream analyses such as the detection of marker genes, the robustness and reliability of classifiers, the assessment of novel analysis algorithms, and might reduce the number of animal experiments and costs in consequence. cscGAN outperforms existing methods for single-cell RNA-seq data generation in quality and hold great promise for the realistic generation and augmentation of other biomedical data types.
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.
Abstract Single-cell-based methods such as flow cytometry or single-cell mRNA sequencing (scRNA-seq) allow deep molecular and cellular profiling of immunological processes. Despite their high ...throughput, however, these measurements represent only a snapshot in time. Here, we explore how longitudinal single-cell-based datasets can be used for deterministic ordinary differential equation (ODE)-based modelling to mechanistically describe immune dynamics. We derived longitudinal changes in cell numbers of colonic cell types during inflammatory bowel disease (IBD) from flow cytometry and scRNA-seq data of murine colitis using ODE-based models. Our mathematical model generalised well across different protocols and experimental techniques, and we hypothesised that the estimated model parameters reflect biological processes. We validated this prediction of cellular turnover rates with KI-67 staining and with gene expression information from the scRNA-seq data not used for model fitting. Finally, we tested the translational relevance of the mathematical model by deconvolution of longitudinal bulk mRNA-sequencing data from a cohort of human IBD patients treated with olamkicept. We found that neutrophil depletion may contribute to IBD patients entering remission. The predictive power of IBD deterministic modelling highlights its potential to advance our understanding of immune dynamics in health and disease.
T regulatory type 1 (Tr1) cells, which are defined by their regulatory function, lack of Foxp3, and high expression of IL-10, CD49b, and LAG-3, are known to be able to suppress Th1 and Th17 in the ...intestine. Th1 and Th17 cells are also the main drivers of crescentic glomerulonephritis (GN), the most severe form of renal autoimmune disease. However, whether Tr1 cells emerge in renal inflammation and, moreover, whether they exhibit regulatory function during GN have not been thoroughly investigated yet. To address these questions, we used a mouse model of experimental crescentic GN and double Foxp3mRFP IL-10eGFP reporter mice. We found that Foxp3neg IL-10-producing CD4+ T cells infiltrate the kidneys during GN progression. Using single-cell RNA sequencing, we could show that these cells express the core transcriptional factors characteristic of Tr1 cells. In line with this, Tr1 cells showed a strong suppressive activity ex vivo and were protective in experimental crescentic GN in vivo. Finally, we could also identify Tr1 cells in the kidneys of patients with antineutrophil cytoplasmic autoantibody-associated GN and define their transcriptional profile. Tr1 cells are currently used in several immune-mediated inflammatory diseases, such as T-cell therapy. Thus, our study provides proof of concept for Tr1 cell-based therapies in experimental GN.
Significance Statement
CD4
+
IL-17A–producing CD4
+
T helper (T
H
17) cells play a unique role in autoimmune and chronic inflammatory diseases of the kidney, skin, and gut. Their proinflammatory ...functions are mediated through the release of IL-17A and -F, which activate the IL-17 receptor A (IL-17RA) and IL-17RC signaling pathways in epithelial and endothelial cells. We report that the IL-17RA/IL-17RC complex is highly expressed in CD4
+
T
H
17 cells. Disruption of the IL-17R signaling pathway in these cells potentiates T
H
17 cell pathogenicity and accelerates experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis. These findings indicate that IL-17 receptor signaling controls the T
H
17 response
via
the IL-17RA/IL-17RC complex through a self-inhibitory loop in immune-mediated diseases and might provide new insights into the development of more efficient anti-T
H
17 treatment strategies.
Background
IL-17A–producing CD4
+
T helper (T
H
17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells,
e.g.
, CD4
+
T cell subsets, remains to be elucidated.
Methods
Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFN
γ
, and Foxp3 triple-reporter mice for sorting of renal CD4
+
T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated T
H
17 cell–specific IL-17RA and IL-17RC gene–deficient mice and studied the functional role of IL-17 signaling in T
H
17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4
+
CD45RB
high
T cell transfer colitis model.
Results
We identified a specific expression of the IL-17 receptor A/C complex on CD4
+
T
H
17 cells. Single-cell RNA sequencing of T
H
17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4
+
T cells and, most importantly, specifically in CD4
+
T
H
17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis.
Conclusions
Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4
+
T
H
17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T
H
17 treatment strategies.
The detection of vague, speculative, or otherwise uncertain language has been performed in the encyclopedic, political, and scientific domains yet left relatively untouched in finance. However, the ...latter benefits from public sources of big financial data that can be linked with extracted measures of linguistic uncertainty as a mean of extrinsic model validation. Doing so further helps in understanding how the linguistic uncertainty of financial disclosures might induce financial uncertainty to the market. To explore this field, we use term weighting methods to detect linguistic uncertainty in a large dataset of financial disclosures. As a baseline, we use an existing dictionary of financial uncertainty triggers; furthermore, we retrieve related terms in specialized word embedding models to automatically expand this dictionary. Apart from an industry-agnostic expansion, we create expansions incorporating industry-specific jargon. In a set of cross-sectional event study regressions, we show that the such enriched dictionary explains a significantly larger share of future volatility, a common financial uncertainty measure, than before. Furthermore, we show that—different to the plain dictionary—our embedding models are well suited to explain future analyst forecast uncertainty. Notably, our results indicate that enriching the dictionary with industry-specific vocabulary explains a significantly larger share of financial uncertainty than an industry-agnostic expansion.
IL-17A-producing CD4
T helper (T
17) cells play a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. The proinflammatory effects of IL-17 are mediated by the ...activation of the IL-17RA/IL-17RC complex. Although the expression of these receptors on epithelial and endothelial cells is well characterized, the IL-17 receptor expression pattern and function on hematopoietic cells,
, CD4
T cell subsets, remains to be elucidated.
Crescentic GN (nephrotoxic nephritis) was induced in IL-17A, IFN
, and Foxp3 triple-reporter mice for sorting of renal CD4
T cell subsets and subsequent single-cell RNA sequencing. Moreover, we generated T
17 cell-specific IL-17RA and IL-17RC gene-deficient mice and studied the functional role of IL-17 signaling in T
17 cells in crescentic GN, imiquimod-induced psoriasis, and in the CD4
CD45RB
T cell transfer colitis model.
We identified a specific expression of the IL-17 receptor A/C complex on CD4
T
17 cells. Single-cell RNA sequencing of T
17 cells revealed the activation of the IL-17 receptor signaling pathway in experimental crescentic GN. Disruption of the IL-17RC signaling pathway in CD4
T cells and, most importantly, specifically in CD4
T
17 cells, potentiates the IL-17 cytokine response and results in an accelerated course of experimental crescentic GN. Comparable results were observed in experimental models of psoriasis and colitis.
Our findings indicate that IL-17 receptor C signaling has a previously unrecognized function in the regulation of CD4
T
17 cells and in the control of organ-specific autoimmunity and might provide new insights into the development of more efficient anti-T
17 treatment strategies.
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