Publications by authors named "Kai Hildner"

42 Publications

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

Nat Commun 2021 02 18;12(1):1112. Epub 2021 Feb 18.

Department of Surgery, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

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. Patients with severe COVID-19 exhibit also reduced circulating plasmacytoid dendritic cells (pDCs) and low plasma IFNα and IFNλ levels when compared to non-severe COVID-19 patients. In a mouse model of pulmonary HSV-1 infection, treatment with recombinant IL-3 reduces viral load and mortality. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating pDCs into the airways by stimulating CXCL12 secretion from pulmonary CD123 epithelial cells, both, in mice and in COVID-19 negative patients exhibiting pulmonary diseases. This study identifies IL-3 as a predictive disease marker for SARS-CoV-2 infections and as a potential therapeutic target for pulmunory viral infections.
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http://dx.doi.org/10.1038/s41467-021-21310-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893044PMC
February 2021

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

Front Immunol 2020 29;11:590893. Epub 2021 Jan 29.

Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.

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. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis . Employing the CD4CD25 naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic but not in colitis-protected mice. Colitis mitigation in T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in T cell receiving mice.
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http://dx.doi.org/10.3389/fimmu.2020.590893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879684PMC
January 2021

Label-Free In Vivo Histopathology of Experimental Colitis via 3-Channel Multiphoton Endomicroscopy.

Gastroenterology 2020 09 13;159(3):832-834. Epub 2020 Jun 13.

Erlangen Graduate School in Advanced Optical Technologies; Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany; Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2020.05.081DOI Listing
September 2020

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

Front Immunol 2020 7;11:691. Epub 2020 May 7.

Department of Medicine 1, University Hospital of Erlangen, Erlangen, Germany.

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. On a functional level, the CCR6 ligand CCL20 was identified as potent promoter of lung-directed ILC2 migration upon inflammatory conditions and using a new humanized mouse model with light-sheet fluorescence microscopic visualization of lung-accumulated human ILC2s. In the lung, blood-derived human ILC2s were able to augment local eosinophil and neutrophil accumulation and induced a marked upregulation of pulmonary type-VI collagen expression. Studies in primary human lung fibroblasts additionally revealed ILC2-derived IL-4 and IL-13 as important mediators of this type-VI collagen-inducing effect. Taken together, the here acquired results suggest that pathologically increased CCL20 levels in cystic fibrosis airways induce CCR6-mediated lung homing of circulating human ILC2s. Subsequent ILC2 activation then triggers local production of type-VI collagen and might thereby drive extracellular matrix remodeling potentially influencing pulmonary tissue destruction in cystic fibrosis patients. Thus, modulating the lung homing capacity of circulating ILC2s and their local effector functions opens new therapeutic avenues for cystic fibrosis treatment.
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http://dx.doi.org/10.3389/fimmu.2020.00691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221160PMC
March 2021

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

Sci Rep 2020 May 26;10(1):8747. Epub 2020 May 26.

Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-65653-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250898PMC
May 2020

Resolution of acute intestinal graft-versus-host disease.

Semin Immunopathol 2019 11 31;41(6):655-664. Epub 2019 Oct 31.

Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.

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. Especially in the presence of intestinal manifestations of GvHD, the risk that the disease takes a life-threatening, potentially fatal course is significantly increased. In the light of a rapid gain of knowledge in respect to decode innate and adaptive immunity related mechanisms as, e.g., cytokine networks, intracellular signaling pathways or environmental triggers as, e.g., the intestinal microbiota and the development of novel therapeutic approaches, detailed insight into endogenous mechanisms seeking to counterbalance the proinflammatory machinery or to proactively foster signals promoting the resolution of allo-driven intestinal inflammation is emerging. Here, we seek to highlight the key aspects of those mechanisms involved in and contributing to the resolution of GvHD-associated intestinal inflammation. Concomitantly, we would like to briefly outline and discuss promising future experimental targets suitable to be therapeutically employed to directionally deflect the tissue response from a proinflammatory to an inflammation-resolving type of intestinal GvHD after allo-HCT.
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http://dx.doi.org/10.1007/s00281-019-00769-wDOI Listing
November 2019

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

Immunology 2020 02 13;159(2):193-204. Epub 2019 Nov 13.

Institute of Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.

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. Here we show that Batf3 mice infected with Plasmodium berghei ANKA (PbA) were protected from experimental CM (ECM), characterized by a stable blood-brain barrier (BBB) and significantly less infiltrated peripheral immune cells in the brain. Importantly, the absence of ECM in Batf3 mice correlated with attenuated responses of cytotoxic T-cells, as their parasite-specific lytic activity as well as the production of interferon gamma and granzyme B were significantly decreased. Remarkably, spleens of ECM-protected Batf3 mice had elevated levels of regulatory immune cells and interleukin 10. Thus, protection from ECM in PbA-infected Batf3 mice was associated with the absence of strong CD8 T-cell activity and induction of immunoregulatory mediators and cells.
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http://dx.doi.org/10.1111/imm.13137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954726PMC
February 2020

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

Front Immunol 2019 26;10:883. Epub 2019 Apr 26.

Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, University of Erlangen-Nuremberg, Erlangen, Germany.

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). Interestingly, clinical studies in patients who underwent allogeneic stem cell transplantation reveal an inverse correlation between the frequency of circulating DN T-cells and the severity of GvHD, suggesting a therapeutic potential of human DN T-cells. However, their exact mode of action has not been elucidated yet. Investigating the impact of DN T-cells on conventional T-cells, we found that human DN T-cells selectively inhibit mTOR signaling in CD4 T-cells. Given that mTOR is a critical regulator of cellular metabolism, we further determined the impact of DN T-cells on the metabolic framework of T-cells. Intriguingly, DN T-cells diminished expression of glucose transporters and glucose uptake, whereas fatty acid uptake was not modified, indicating that DN T-cells prevent metabolic adaptation of CD4 T-cells upon activation (i.e., glycolytic switch) thereby contributing to their suppression. Further analyses demonstrated that CD4 T-cells also do not upregulate homing receptors associated with inflammatory processes. In contrast, expression of central memory-cell associated cell surface markers and transcription factors were increased by DN T-cells. Moreover, CD4 T-cells failed to produce inflammatory cytokines after co-culture with DN T-cells, whereas IL-2 secretion was enhanced. Taken together DN T-cells impair metabolic reprogramming of conventional CD4 T-cells by abrogating mTOR signaling, thereby modulating CD4 T-cell functionality. These results uncover a new mechanism of DN T-cell-mediated suppression, pointing out that DN T-cells could serve as cell-based therapy to limit alloreactive immune response.
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http://dx.doi.org/10.3389/fimmu.2019.00883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498403PMC
September 2020

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

JCI Insight 2019 04 11;5. Epub 2019 Apr 11.

Laboratory of RNA Molecular Biology and.

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. The exRNA pool was dominated by hematopoietic cells and platelets, with additional contribution from the liver. About 60% of the 15- to 42-nt reads originated from the coding sequences, in a pattern reminiscent of ribosome-profiling. Blood sample type had a considerable influence on the exRNA profile. On average approximately 350 to 1,100 distinct ex-mRNA transcripts were detected depending on plasma type. In serum, additional transcripts from neutrophils and hematopoietic cells increased this number to near 2,300. EDTA and ACD plasma showed a destabilizing effect on ex mRNA and non-coding RNA ribonucleoprotein complexes compared to other plasma types. In a proof-of-concept study, we investigated differences between the exRNA profiles of patients with acute coronary syndrome (ACS) and healthy controls. The improved tissue resolution of ex mRNAs after PNK-treatment enabled us to detect a neutrophil-signature in ACS that escaped detection by ex miRNA analysis.
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http://dx.doi.org/10.1172/jci.insight.127317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538341PMC
April 2019

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

Nat Immunol 2019 Apr;20(4):514

Department of Medicine 1, Kussmaul Campus for Medical Research and Translational Research Center, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.

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: "...the Collaborative Research Center TRR241 of the German Research Council (DFG)...". The error has been corrected in the HTML and PDF version of the article.
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http://dx.doi.org/10.1038/s41590-019-0360-yDOI Listing
April 2019

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

J Vis Exp 2019 02 11(144). Epub 2019 Feb 11.

Department of Internal Medicine 1, University Erlangen-Nürnberg, University Hospital Erlangen; Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen;

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. Hence, detailed knowledge about the tissue-resident immune cascade, changes in the intestinal microbiota, and the stromal response prior, upon, and after intestinal GvHD onset are urgently needed to understand the events and mechanisms underlying its pathogenesis and to develop innovative therapeutic options. Murine models of GvHD are frequently employed to identify and functionally assess molecules and pathways putatively driving intestinal GvHD. However, means to specifically monitor and evaluate intestinal inflammation over time are essentially lacking since established scores to assess and grade acute GvHD are routinely comprised of various parameters which rather reflect systemic GvHD manifestations. The detailed evaluation of intestinal GvHD has been restricted to studies using euthanized mice, thereby essentially excluding longitudinal (i.e., kinetic) analyses of the colonic compartment under a given experimental condition (e.g., antibody-mediated blockade of a proinflammatory cytokine) in live mice (i.e., in vivo). The mini-endoscopic in situ assessment of the distal colon of allo-HCT-treated mice described here allows a) a detailed macroscopic evaluation of different aspects of intestinal inflammation and b) the option to collect tissue samples for downstream analyses at various time points over the course of the observation period. Overall, the mini-endoscopic approach provides a major advance in preclinical noninvasive monitoring and assessment of intestinal GvHD.
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http://dx.doi.org/10.3791/58871DOI Listing
February 2019

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

Nat Immunol 2019 03 28;20(3):288-300. Epub 2019 Jan 28.

Department of Medicine 1, Kussmaul Campus for Medical Research and Translational Research Center, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.

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. In vivo, functional impairment of T cells in mice with double knockout of the T-cell-associated transcription factors Hobit and Blimp-1 attenuated disease in several models of colitis, due to impaired cross-talk between the adaptive and innate immune system. Finally, depletion of T cells led to a suppression of colitis activity. Together, our data demonstrate a central role for T cells in the pathogenesis of chronic intestinal inflammation and suggest that these cells could be targets for future therapeutic approaches in IBD.
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http://dx.doi.org/10.1038/s41590-018-0298-5DOI Listing
March 2019

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

PLoS One 2018 26;13(10):e0206576. Epub 2018 Oct 26.

Institute of Radiology, University Hospital Erlangen, Maximiliansplatz 1, Erlangen, Germany.

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. This study relied on colitis induction by Dextran Sodium Sulfate (DSS) and investigated the colon of mice in vivo as well as ex vivo. Receiver Operating Characteristics were used to calculate sensitivity, specificity, positive- and negative-predictive values (PPV and NPV) of these single values in detecting DSS-treatment as a reference condition. A Model Averaged Neural Network (avNNet) was trained on the multiparametric combination of the measured values, and its predictive capacity was compared to those of the single parameters using exact binomial tests. Within the in vivo subgroup (n = 19), the avNNet featured a sensitivity of 91.3% (95% CI: 86.6-96.0%), specificity of 92.3% (95% CI: 85.1-99.6%), PPV of 96.9% (94.0-99.9%) and NPV of 80.0% (95% CI: 69.9-90.1%), significantly outperforming all single parameters in at least 2 accuracy measures (p < 0.003) and performing significantly worse compared to none of the single values. Within the ex vivo subgroup (n = 30), the avNNet featured a sensitivity of 87.4% (95% CI: 82.6-92.2%), specificity of 82.9% (95% CI: 76.1-89.7%), PPV of 88.9% (84.3-93.5%) and NPV of 80.8% (95% CI: 73.8-87.9%), significantly outperforming all single parameters in at least 2 accuracy measures (p < 0.015), exceeded by none of the single parameters. In experimental mouse colitis, multiparametric MRI and the combination of several single measured values to an avNNet can significantly increase diagnostic accuracy compared to the single parameters alone. This pilot study will provide new avenues for the development of an MR-derived colitis score for optimized diagnosis and surveillance of inflammatory bowel disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206576PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203400PMC
March 2019

Confocal Laser Endomicroscopy for Diagnosing Malignant Pleural Effusions.

Med Sci Monit 2018 Aug 5;24:5437-5447. Epub 2018 Aug 5.

Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.

BACKGROUND Confocal laser endomicroscopy (CLE) enables "in vivo" microscopic tissue diagnosis based on tissue reflectance or tissue fluorescence upon application of fluorescence agents. The aim of the present study was to evaluate CLE as a new diagnostic approach for differentiation between malignant versus non-malignant pleural effusions. MATERIAL AND METHODS In 100 patients with pleural effusions, thoracentesis was performed. Cresyl violet and acriflavine were used as contrast agents for probe-based CLE of effusions. CLE video sequences were assessed by 4 independent investigators (2 experienced in this technique, 2 with only basic knowledge). In addition, all CLE samples were evaluated by an expert pathologist (p). Results were compared with conventional cytology of effusions and histology of cell blocks. RESULTS CLE reliably permitted identification of malignant cells in pleural effusions. Sensitivity for detection of malignant effusions was 87% (p: 87%) and 81% (p: 72%) for acriflavine and cresyl violet, respectively. With regard to specificity, acriflavine and cresyl violet yielded a mean value of 99% (p: 100%) and 92% (p: 100%). CONCLUSIONS In this pilot study, CLE permitted simple and rapid detection of malignant pleural effusions. Larger prospective studies are warranted to corroborate our findings.
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http://dx.doi.org/10.12659/MSM.909989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091162PMC
August 2018

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

Front Immunol 2018 25;9:1138. Epub 2018 May 25.

Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.

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. Interestingly, we recently identified granulocyte-macrophage colony-stimulating factor (GM-CSF) T cells to be promoted by interleukin-7 (IL-7) signaling and controlled by the activating protein-1 transcription factor family member basic leucine zipper transcription factor ATF-like (BATF) as critical mediators of intestinal GvHD in mice. Given the dual role of BATF, the contribution of IL-23-mediated signaling within donor T cells and bona fide Th17 cells remains to be delineated from the regulation of GM-CSF T cells in the absence of BATF. Here, we found in a complete MHC class I-mismatched model that genetic inactivation of the IL-23 receptor (IL-23R) or the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) within donor T cells similarly ablated Th17 cell formation but preserved the T cells' ability to induce intestinal GvHD in a compared to wild-type controls indistinguishable manner. Importantly, RORγt-independent manifestation of intestinal GvHD was completely dependent on BATF-regulated GM-CSF T cells as BATF/RORγt double-deficient T cells failed to induce colitis and the antibody-mediated blockage of IL-7/IL-7R interaction and GM-CSF significantly diminished signs of intestinal GvHD elicited by RORγt-deficient donor T cells. Finally, in analogy to our murine studies, colonic expression levels inversely correlated with the presence of GvHD in allo-HSCT patients. Together, this study provides a crucial example of a BATF-dependent, however, IL-23R signaling- and RORγt-, i.e., Th17 fate-independent regulation of a colitogenic T cell population critically impacting the current understanding of intestinal GvHD.
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http://dx.doi.org/10.3389/fimmu.2018.01138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992389PMC
July 2019

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

Gut 2019 05 30;68(5):814-828. Epub 2018 May 30.

First Department of Medicine, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

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.

Design: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS.

Results: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23.

Conclusions: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.
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http://dx.doi.org/10.1136/gutjnl-2017-315671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580782PMC
May 2019

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

J Clin Invest 2018 03 29;128(3):916-930. Epub 2018 Jan 29.

Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.

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. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility-mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor-positive (IL-7R+), granulocyte-macrophage colony-stimulating factor-positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell-intrinsic BATF expression, required IL-7-IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 driven.
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http://dx.doi.org/10.1172/JCI89242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824870PMC
March 2018

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

Dig Dis 2016;34 Suppl 1:40-7. Epub 2016 Aug 22.

Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany.

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. In line with this hypothesis, a series of preclinical studies have unequivocally established that T cells are key drivers of immune-mediated colitis. Interestingly, especially Th17 cells were identified to be highly prevalent in inflamed IBD tissues, a finding that seems to be functionally relevant as genetic inactivation studies in the mouse resulted in almost complete suppression of colitis development.

Key Messages: While targeting Th17 cell differentiation regulating transcription factors, as retinoic acid-related orphan receptor gamma t (RORγt) is effective in preventing murine colitis, one concern of drugs targeting RORγt in a clinical setting represents the large body of murine data unambiguously demonstrating that additional pathways within and outside the immune system are equally RORγt-dependent increasing the risk of undesirable side effects. The AP1 transcription factor Batf (B cell-activating transcription factor) appears to exclusively regulate pathways within lymphocytes. Importantly, Batf represents a central regulator of Th17 cell development and is strongly upregulated within IBD-affected tissues. Employing 2 acute colitis models, we demonstrate in this study that Batf-expressing T cells are critical drivers of T cell-mediated colitis while in contrast to Stat3 loss of Batf does not affect intestinal epithelial cell homeostasis ex vivo.

Conclusions: Targeting Batf in IBD emerges as an attractive therapeutic approach disabling colitogenic T cell activities while sparing off-target effects in the intestinal epithelial cell compartment.
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http://dx.doi.org/10.1159/000447281DOI Listing
January 2017

Ablation of CD8α(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice.

Sci Rep 2015 Oct 21;5:15414. Epub 2015 Oct 21.

Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands.

Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization. Ldlr(-/-) mice were transplanted with batf3(-/-) or wt bone marrow and put on a western type diet. Hematopoietic batf3 deficiency sharply decreased CD8α(+) DC numbers in spleen and lymph nodes (>80%; P < 0,001). Concordantly, batf3(-/-) chimeras had a 75% reduction in OT-I cross-priming capacity in vivo. Batf3(-/-) chimeric mice did not show lower Tcell or other leukocyte subset numbers. Despite dampened cross-presentation capacity, batf3(-/-) chimeras had equal atherosclerosis burden in aortic arch and root. Likewise, batf3(-/-) chimeras and wt mice revealed no differences in parameters of plaque stability: plaque Tcell infiltration, cell death, collagen composition, and macrophage and vascular smooth muscle cell content were unchanged. These results show that CD8α(+) DC loss in hyperlipidemic mice profoundly reduces cross-priming ability, nevertheless it does not influence lesion development. Taken together, we clearly demonstrate that CD8α(+) DC-mediated cross-presentation does not significantly contribute to atherosclerotic plaque formation and stability.
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http://dx.doi.org/10.1038/srep15414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614009PMC
October 2015

Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer.

Gut 2016 07 2;65(7):1139-50. Epub 2015 Apr 2.

Department of Medicine 1, University Hospital Erlangen, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, Erlangen, Germany Max Eder Research Group supported by the German Cancer Aid, University Hospital Erlangen, Erlangen, Germany.

Objectives: IBDs have an increased risk for development of colorectal cancer (CRC). Here, we aimed at the characterisation of the functional role of Th17-associated transcription factors in sporadic and colitis-associated colon cancer in vivo.

Design: We used mice deficient or transgenic for the activating protein 1 family member basic leucine zipper transcription factor ATF-like (Batf) to evaluate the role of Th17 cells during sporadic and inflammation-induced colon carcinogenesis. We also studied the expression of Batf and RORγt in patients with IBD and CRC.

Results: Batf but not retinoic acid-related orphan receptor γt(RORγt) expression was significantly increased together with interleukin (IL) 23 expression in UC but not in Crohn's disease (CD) tissue samples. In CRC also Batf but not RORγt expression was increased and its expression correlated with the IL-23 and IL-23 receptor (IL-23R) expression. Finally, Batf but not RORγt was coexpressed with IL-17a, IL-23R and IL-6 within CRC-infiltrating CD4(+) T cells. Functional studies in mice revealed that Batf-dependent T cells are crucial regulators of sporadic and inflammation-induced CRC. Colitis-associated Batf(-/-) tumours lacked IL-17a(+)IL-23R(+)IL-6(+)CD4(+) T cells, hence displaying characteristics reminiscent of human CRC-infiltrating CD4(+) T cells. Strikingly, Batf(-/-) tumours contained low IL-23 but high IL-17a expression levels. Tumour formation and intratumoral IL-23 expression could be restored by administration of Hyper-IL-6 consisting of IL-6 and soluble IL-6 receptor.

Conclusions: Batf-dependent IL-23R(+)IL-6(+)CD4(+) Th17 cells critically control IL-23 driven colitis-associated tumour formation and the progression of sporadic colon tumours. Batf-dependent IL-23R(+) T cells represent a potential future therapeutic target limiting CRC progression.
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http://dx.doi.org/10.1136/gutjnl-2014-308227DOI Listing
July 2016

STAT3 activation in Th17 and Th22 cells controls IL-22-mediated epithelial host defense during infectious colitis.

J Immunol 2014 Oct 3;193(7):3779-91. Epub 2014 Sep 3.

Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany;

The Citrobacter rodentium model mimics the pathogenesis of infectious colitis and requires sequential contributions from different immune cell populations, including innate lymphoid cells (ILCs) and CD4(+) lymphocytes. In this study, we addressed the role of STAT3 activation in CD4(+) cells during host defense in mice against C. rodentium. In mice with defective STAT3 in CD4(+) cells (Stat3(ΔCD4)), the course of infection was unchanged during the innate lymphoid cell-dependent early phase, but significantly altered during the lymphocyte-dependent later phase. Stat3(ΔCD4) mice exhibited intestinal epithelial barrier defects, including downregulation of antimicrobial peptides, increased systemic distribution of bacteria, and prolonged reduction in the overall burden of C. rodentium infection. Immunomonitoring of lamina propria cells revealed loss of virtually all IL-22-producing CD4(+) lymphocytes, suggesting that STAT3 activation was required for IL-22 production not only in Th17 cells, but also in Th22 cells. Notably, the defective host defense against C. rodentium in Stat3(∆CD4) mice could be fully restored by specific overexpression of IL-22 through a minicircle vector-based technology. Moreover, expression of a constitutive active STAT3 in CD4(+) cells shaped strong intestinal epithelial barrier function in vitro and in vivo through IL-22, and it promoted protection from enteropathogenic bacteria. Thus, our work indicates a critical role of STAT3 activation in Th17 and Th22 cells for control of the IL-22-mediated host defense, and strategies expanding STAT3-activated CD4(+) lymphocytes may be considered as future therapeutic options for improving intestinal barrier function in infectious colitis.
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http://dx.doi.org/10.4049/jimmunol.1303076DOI Listing
October 2014

The activating protein 1 transcription factor basic leucine zipper transcription factor, ATF-like (BATF), regulates lymphocyte- and mast cell-driven immune responses in the setting of allergic asthma.

J Allergy Clin Immunol 2014 Jan 28;133(1):198-206.e1-9. Epub 2013 Nov 28.

Department of Molecular Pneumology, University of Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

Background: Mice without the basic leucine zipper transcription factor, ATF-like (BATF) gene (Batf(-/-)) lack TH17 and follicular helper T cells, which demonstrates that Batf is a transcription factor important for T- and B-cell differentiation.

Objective: In this study we examined whether BATF expression would influence allergic asthma.

Methods: In a cohort of preschool control children and children with asthma, we analyzed BATF mRNA expression using real-time PCR in PBMCs. In a murine model of allergic asthma, we analyzed differences in this allergic disease between wild-type, Batf transgenic, and Batf(-/-) mice.

Results: In the absence of corticosteroid treatment, children with recurrent asthma have a significant increase in BATF mRNA expression in their PBMCs. Batf(-/-) mice display a significant reduction in the pathophysiologic responses seen in asthmatic wild-type littermates. Moreover, we discovered a decrease in IL-3 production and IL-3-dependent mast cell development in Batf(-/-) mice. By contrast, IFN-γ was induced in lung CD4(+) and CD8(+) T cells. Intranasal delivery of anti-IFN-γ antibodies induced airway hyperresponsiveness and inflammation in wild-type but not in Batf(-/-) mice. Transgenic overexpression of Batf under the control of the CD2 promoter/enhancer augmented lung inflammation and IgE levels in the setting of experimental asthma.

Conclusion: BATF is increased in non-steroid-treated asthmatic children. Targeting BATF expression resulted in amelioration of the pathophysiologic responses seen in children with allergic asthma, and BATF has emerged as a novel target for antiasthma interventions.
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http://dx.doi.org/10.1016/j.jaci.2013.09.049DOI Listing
January 2014

Public spirometry for primary prevention of COPD.

J Eval Clin Pract 2014 Feb 17;20(1):43-7. Epub 2013 Aug 17.

Division of Respiratory Medicine, Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: The most effective action for primary prevention of chronic obstructive lung disease is smoking cessation early enough. In secondary prevention, smokers with airway obstruction were more likely to quit smoking. The aim of this study was to evaluate the impact of a public spirometry on smoking habits in terms of primary prevention.

Methods: Spirometry with its medical analysis was offered to visitors of a local public event called 'Lange Nacht der Wissenschaften' ('Long night of sciences'). The impact of results on smoking habits was evaluated in all smokers with an anonymized questionnaire afterwards.

Results: Two hundred fifty-seven people with the median age of 30 years (interquartile range 22-46) were examined. Out of 44 current smokers (17.1%), only two individuals showed a prebronchodilator FEV1/forced vital capacity-value <0.7. Fourteen smokers stated to have an increased motivation to quit smoking whereas 28 smokers declared that their motivation to quit smoking was independent of spirometry result. These smokers were significantly younger (median age 28 vs. 40 years, P = 0.025) without differences in spirometry results or smoking habits.

Conclusion: In an unselected population with a high amount of younger adults, normal spirometry did not show a short-term benefit for primary prevention of chronic obstructive lung disease in terms of increasing motivation to quit smoking.
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http://dx.doi.org/10.1111/jep.12077DOI Listing
February 2014

Confocal laser endomicroscopy for diagnosing lung cancer in vivo.

Eur Respir J 2013 Jun 20;41(6):1401-8. Epub 2012 Sep 20.

Dept of Medicine 1, University of Erlangen–Nuremberg, Erlangen, Germany.

Confocal laser endomicroscopy is a novel endoscopic technique that may allow imaging of living cells in lung tissue in vivo. We assessed the potential of this technique for the detection of histology during screening bronchoscopy for lung cancer. 32 patients with suspected malignancies underwent bronchoscopy with endomicroscopy using acriflavine hydrochloride. Standardised areas and localised lesions were analysed by in vivo confocal imaging during bronchoscopy and biopsies were taken. Confocal images were graded and correlated prospectively with conventional histology from biopsies. Acriflavine hydrochloride yielded high-quality confocal images and strongly labelled airway epithelial cells. No side-effects were noted. 75,522 confocal images from 56 different locations were compared prospectively with histological data from biopsy specimens. Endomicroscopy allowed subsurface imaging with detailed analysis of cellular and subcellular structures. Neoplastic changes could be predicted with high accuracy (sensitivity 96.0%, specificity 87.1%, accuracy 91.0%). Confocal laser endomicroscopy with acriflavine is a novel diagnostic tool for the analysis of living cells during bronchoscopy and permits virtual histology of neoplastic changes in the airways with high accuracy. This technique may enable the rapid diagnosis of neoplasia during ongoing endoscopy in patients with suspected lung cancer.
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http://dx.doi.org/10.1183/09031936.00062512DOI Listing
June 2013

Methylene blue-aided in vivo staining of central airways during flexible bronchoscopy.

ScientificWorldJournal 2012 1;2012:625867. Epub 2012 Aug 1.

Department of Medicine, University of Erlangen-Nuremberg, Ulmenweg 18, 91054 Erlangen, Germany.

Background: The early diagnosis of malignant and premalignant changes of the bronchial mucosa remains a major challenge during bronchoscopy. Intravital staining techniques are not new. Previous small case series suggested that analysis of the bronchial mucosal surface using chromoendoscopy allows a prediction between neoplastic and nonneoplastic lesions.

Objectives: The aim of the present study was to evaluate chromobronchoscopy as a method to identify malignant and premalignant lesions in the central airways in a prospective manner.

Methods: In 26 patients we performed chromoendoscopy with 0.1% methylene blue during ongoing flexible white light bronchoscopy. Circumscribed lesions in central airways were further analyzed by biopsies and histopathologic examination.

Results: In the majority of cases neither flat nor polypoid lesions in the central airways were stained by methylene blue. In particular, exophytic growth of lung cancer did not show any specific pattern in chromobronchoscopy. However, a specific dye staining was detected in one case where exophytic growth of metastatic colorectal cancer was present in the right upper lobe. In two other cases, a circumscribed staining was noted in unsuspicious mucosa. But histology revealed inflammation only.

Conclusions: In contrast to previous studies, the present findings clearly indicate that chromobronchoscopy is not useful for early detection of malignant or premalignant lesions of the central airways.
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http://dx.doi.org/10.1100/2012/625867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415176PMC
March 2013

A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage.

Cell 2012 Mar;148(5):1001-14

Institute of Molecular Medicine and Max-Planck-Research Department of Stem Cell Aging, University of Ulm, Ulm, Germany.

Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and γ-irradiation. DNA damage induces BATF in a G-CSF/STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to γ-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.
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http://dx.doi.org/10.1016/j.cell.2012.01.040DOI Listing
March 2012

Batf3-dependent CD11b(low/-) peripheral dendritic cells are GM-CSF-independent and are not required for Th cell priming after subcutaneous immunization.

PLoS One 2011 17;6(10):e25660. Epub 2011 Oct 17.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Dendritic cells (DCs) subsets differ in precursor cell of origin, functional properties, requirements for growth factors, and dependence on transcription factors. Lymphoid-tissue resident CD8α(+) conventional DCs (cDCs) and CD11b(low/-)CD103(+) non-lymphoid DCs are developmentally related, each being dependent on FMS-like tyrosine kinase 3 ligand (Flt3L), and requiring the transcription factors Batf3, Irf8, and Id2 for development. It was recently suggested that granulocyte/macrophage colony stimulating factor (GM-CSF) was required for the development of dermal CD11b(low/-)Langerin(+)CD103(+) DCs, and that this dermal DC subset was required for priming autoreactive T cells in experimental autoimmune encephalitis (EAE). Here, we compared development of peripheral tissue DCs and susceptibility to EAE in GM-CSF receptor deficient (Csf2rb(-/-)) and Batf3(-/-) mice. We find that Batf3-dependent dermal CD11b(low/-)Langerin(+) DCs do develop in Csf2rb(-/-) mice, but that they express reduced, but not absent, levels of CD103. Further, Batf3(-/-) mice lacking all peripheral CD11b(low/-) DCs show robust Th cell priming after subcutaneous immunization and are susceptible to EAE. Our results suggest that defective T effector priming and resistance to EAE exhibited by Csf2rb(-/-) mice does not result from the absence of dermal CD11b(low/-)Langerin(+)CD103(+) DCs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0025660PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196467PMC
March 2012

Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14⁺ macrophages.

Gastroenterology 2011 Dec 27;141(6):2026-38. Epub 2011 Aug 27.

Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany.

Background & Aims: The anti-tumor necrosis factor (TNF) antibodies infliximab, adalimumab, and certolizumab pegol have proven clinical efficacy in Crohn's disease. Here, we assessed the effects of anti-TNF antibodies on apoptosis in inflammatory bowel disease (IBD).

Methods: CD14(+) macrophages and CD4(+) T cells were isolated from peripheral blood and lamina propria mononuclear cells from patients with IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and fluorescence-activated cell sorting techniques.

Results: Lamina propria CD14(+) macrophages showed significantly more frequent and higher membrane-bound TNF (mTNF) expression than CD4(+) T cells in IBD, whereas mTNF-dependent signaling proteins such as TNF receptor (TNFR) 2, TNFR-associated factor (TRAF) 2, and nuclear factor κB were induced in IBD mucosal CD4(+) T cells. Most anti-TNF antibodies did not induce T-cell apoptosis in purified peripheral or mucosal CD4(+) T cells. However, in contrast to etanercept, administration of all clinically effective anti-TNF antibodies resulted in a significant induction of T-cell apoptosis in IBD when lamina propria CD4(+) T cells expressing TNFR2(+) were cocultured with mTNF(+) CD14(+) intestinal macrophages. In contrast, no effects in control patients were noted. T-cell apoptosis in IBD occurred in vivo after treatment with adalimumab and infliximab, was critically dependent on TNFR2 signaling, and could be prevented via interleukin-6 signal transduction. Blockade of interleukin-6R signaling augmented anti-TNF-induced T-cell apoptosis in IBD.

Conclusions: Clinically effective anti-TNF antibodies are able to induce T-cell apoptosis in IBD only when mucosal TNFR2(+) T cells are cocultured with mTNF-expressing CD14(+) macrophages. The finding that anti-TNF antibodies induce apoptosis indirectly by targeting the mTNF/TNFR2 pathway may have important implications for the development of new therapeutic strategies in IBD.
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http://dx.doi.org/10.1053/j.gastro.2011.08.032DOI Listing
December 2011

CD8α(+) dendritic cells are an obligate cellular entry point for productive infection by Listeria monocytogenes.

Immunity 2011 Aug;35(2):236-48

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

CD8α(+) dendritic cells (DCs) prime cytotoxic T lymphocytes during viral infections and produce interleukin-12 in response to pathogens. Although the loss of CD8α(+) DCs in Batf3(-/-) mice increases their susceptibility to several pathogens, we observed that Batf3(-/-) mice exhibited enhanced resistance to the intracellular bacterium Listeria monocytogenes. In wild-type mice, Listeria organisms, initially located in the splenic marginal zone, migrated to the periarteriolar lymphoid sheath (PALS) where they grew exponentially and induced widespread lymphocyte apoptosis. In Batf3(-/-) mice, however, Listeria organisms remain trapped in the marginal zone, failed to traffic into the PALS, and were rapidly cleared by phagocytes. In addition, Batf3(-/-) mice, which lacked the normal population of hepatic CD103(+) peripheral DCs, also showed protection from liver infection. These results suggest that Batf3-dependent CD8α(+) and CD103(+) DCs provide initial cellular entry points within the reticuloendothelial system by which Listeria establishes productive infection.
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http://dx.doi.org/10.1016/j.immuni.2011.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172670PMC
August 2011