Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.

Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation.

Novel T cell/organoid culture system allows modeling of intestinal graft-versus-host disease.

Acute graft-versus-host disease (GvHD) remains the biggest clinical challenge and prognosis-determining complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Donor T cells are acceptedly key mediators of alloreactivity against host tissues and here especially the gut. In support of previous studies, we found that the intestinal intra-epithelial lymphocyte (IEL) compartment was dynamically regulated in the course of MHC class I full mismatch allo-HSCT.

High-throughput Raman spectroscopy allows characterization of murine small intestinal intra-epithelial lymphocytes (IEL).

T cells are considered to be critical drivers of intestinal inflammation in mice and people. The so called intra-epithelial lymphocyte (IEL) compartment largely consist of T cells. Interestingly, the specific regulation and contribution of IELs in the context of inflammatory bowel disease remains poorly understood, in part due to the lack of appropriate analysis tools.

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine.

Introduction: Macrophages play an important role in intestinal wound healing. However, the trajectories from circulating monocytes to gut macrophages are incompletely understood.

Methods: Taking advantage of mice depleted for non-classical monocytes due to deficiency for the transcription factor Nr4a1, we addressed the relevance of non-classical monocytes for large intestinal wound healing using flow cytometry, in vivo wound healing assays and immunofluorescence.

Label-Free Characterization and Quantification of Mucosal Inflammation in Common Murine Colitis Models With Multiphoton Imaging.

Background: Clinical challenges in inflammatory bowel diseases require microscopic in vivo evaluation of inflammation. Here, label-free imaging holds great potential, and recently, our group demonstrated the advantage of using in vivo multiphoton endomicroscopy for longitudinal animal studies. This article extends our previous work by in-depth analysis of label-free tissue features in common colitis models quantified by the multiphoton colitis score (MCS).

Dynamic Imaging of IEL-IEC Co-Cultures Allows for Quantification of CD103-Dependent T Cell Migration.

Intraepithelial lymphocytes (IEL) are widely distributed within the small intestinal epithelial cell (IEC) layer and represent one of the largest T cell pools of the body. While implicated in the pathogenesis of intestinal inflammation, detailed insight especially into the cellular cross-talk between IELs and IECs is largely missing in part due to lacking methodologies to monitor this interaction. To overcome this shortcoming, we employed and validated a murine IEL-IEC (organoids) ex vivo co-culture model system.

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. In a prospective multicentric study, we identify IL-3 as an independent prognostic marker for the outcome during SARS-CoV-2 infections. Specifically, low plasma IL-3 levels is associated with increased severity, viral load, and mortality during SARS-CoV-2 infections.

Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell- Manner.

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells.

ILC2 Lung-Homing in Cystic Fibrosis Patients: Functional Involvement of CCR6 and Impact on Respiratory Failure.

Cystic fibrosis patients suffer from a progressive, often fatal lung disease, which is based on a complex interplay between chronic infections, locally accumulating immune cells and pulmonary tissue remodeling. Although group-2 innate lymphoid cells (ILC2s) act as crucial initiators of lung inflammation, our understanding of their involvement in the pathogenesis of cystic fibrosis remains incomplete. Here we report a marked decrease of circulating CCR6 ILC2s in the blood of cystic fibrosis patients, which significantly correlated with high disease severity and advanced pulmonary failure, strongly implicating increased ILC2 homing from the peripheral blood to the chronically inflamed lung tissue in cystic fibrosis patients.

Author Correction: Ablation of CD8α dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Resolution of acute intestinal graft-versus-host disease.

Allogeneic transplantation of hematopoietic stem cells (allo-HCT) represents an increasingly employed therapeutic approach to potentially cure patients suffering from life-threatening malignant and autoimmune disorders. Despite its lifesaving potential, immune-mediated allo-reactivity inherent to the allogeneic transplantation can be observed within up to 50% of all allo-HCT patients regularly resulting in the manifestation of acute and/or chronic graft-versus-host disease (GvHD). Mechanistically, especially donor T cells are assumed to chiefly drive inflammation that can occur in virtually all organs, with the skin, liver, and gut representing as the most frequently affected anatomic sites.

Protection of Batf3-deficient mice from experimental cerebral malaria correlates with impaired cytotoxic T-cell responses and immune regulation.

Excessive inflammatory immune responses during infections with Plasmodium parasites are responsible for severe complications such as cerebral malaria (CM) that can be studied experimentally in mice. Dendritic cells (DCs) activate cytotoxic CD8 T-cells and initiate immune responses against the parasites. Batf3 mice lack a DC subset, which efficiently induces strong CD8 T-cell responses by cross-presentation of exogenous antigens.

Human Double-Negative Regulatory T-Cells Induce a Metabolic and Functional Switch in Effector T-Cells by Suppressing mTOR Activity.

The recently discovered population of TCRαβ+ CD4-/CD8- (double-negative, DN) T-cells are highly potent suppressor cells in mice and humans. In preclinical transplantation models, adoptive transfer of DN T-cells specifically inhibits alloreactive T-cells and prevents transplant rejection or graft-vs.-host disease (GvHD).

Detection of circulating extracellular mRNAs by modified small-RNA-sequencing analysis.

Extracellular mRNAs (ex-mRNAs) potentially supersede extracellular miRNAs (ex-miRNAs) and other RNA classes as biomarkers. We performed conventional small-RNA-sequencing (sRNA-seq) and sRNA-seq with T4 polynucleotide kinase (PNK) end-treatment of total exRNA isolated from serum and platelet-poor EDTA, ACD, and heparin plasma to study the effect on ex-mRNA capture. Compared to conventional sRNA-seq PNK-treatment increased the detection of informative ex-mRNAs reads up to 50-fold.

Author Correction: Hobit- and Blimp-1-driven CD4 tissue-resident memory T cells control chronic intestinal inflammation.

In the version of this article initially published, a portion of the Acknowledgements section ("the Clinical Research Group CEDER of the German Research Council (DFG)") was incorrect. The correct statement is as follows: "..

Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice.

Acute graft-versus-host disease (GvHD) represents the most severe complication that patients previously undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) face and is frequently associated with a poor clinical outcome. While, for instance, GvHD manifestations of the skin are usually responsive to established immune-suppressive therapies and are, hence, not taking a fatal course, the presence and the intensity of intestinal GvHD, especially of the mid-to-lower parts of the gut, strongly influence the outcome and overall survival of patients with acute GvHD. Therapeutic options are essentially limited to the classic immune-suppressive agents yielding only moderate disease-mitigating effects.

Hobit- and Blimp-1-driven CD4 tissue-resident memory T cells control chronic intestinal inflammation.

Although tissue-resident memory T cells (T cells) have been shown to regulate host protection in infectious disorders, their function in inflammatory bowel disease (IBD) remains to be investigated. Here we characterized T cells in human IBD and in experimental models of intestinal inflammation. Pro-inflammatory T cells accumulated in the mucosa of patients with IBD, and the presence of CD4CD69CD103 T cells was predictive of the development of flares.

Application of machine learning algorithms for multiparametric MRI-based evaluation of murine colitis.

Magnetic resonance imaging (MRI) allows non-invasive evaluation of inflammatory bowel disease (IBD) by assessing pathologically altered gut. Besides morphological changes, relaxation times and diffusion capacity of involved bowel segments can be obtained by MRI. The aim of this study was to assess the use of multiparametric MRI in the diagnosis of experimentally induced colitis in mice, and evaluate the diagnostic benefit of parameter combinations using machine learning.

Targeting Inflammatory T Helper Cells Retinoic Acid-Related Orphan Receptor Gamma t Is Ineffective to Prevent Allo-Response-Driven Colitis.

Intestinal graft-versus-host disease (GvHD) is a life-threatening, inflammatory donor T cell-mediated complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the light of the reported efficacy of interleukin-23 (IL-23)-blockade to mitigate syngeneic intestinal inflammation in inflammatory bowel disease patients, targeting IL-23 and thereby interleukin-17a (IL-17a) producing T helper (Th17) cells as the T cell subset assumed to be mostly regulated by IL-23, has emerged as a putatively general concept to harness immune-mediated mucosal inflammation irrespective of the underlying trigger. However, the role of Th17 cells during allo-response driven colitis remains ambiguous due to a series of studies with inconclusive results.

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease.

Objective: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy.

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease.

Acute graft-versus-host disease (GVHD) represents a severe, T cell-driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue-infiltrating Th cell subsets remain to be fully elucidated.

Immunopathogenesis of IBD: Batf as a Key Driver of Disease Activity.

Background: Inflammatory bowel diseases (IBDs) represent a group of chronic immune-mediated disorders that are influenced by a genetic predisposition and additional environmental triggers. Genome-wide association studies strongly implicate that a number of immune system-related genetic variations are critically contributing to the initiation and promotion of intestinal inflammation. Especially the identification of the strong association of a series of single nucleotide polymorphisms including interleukin (IL)-23R, CCR6, signal transducer and activator of transcription 3 (Stat3) and Stat4 with IBD susceptibility point at a critical involvement of T cells and especially of IL-17a-producing Th17 cells in the immune pathogenesis of IBD.