Publications by authors named "Nicola Gagliani"

77 Publications

CD73-mediated adenosine production by CD8 T cell-derived extracellular vesicles constitutes an intrinsic mechanism of immune suppression.

Nat Commun 2021 10 8;12(1):5911. Epub 2021 Oct 8.

Department of Immunology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.

Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. The stepwise hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 generates adenosine, a potent immune suppressor. Here we report that human effector CD8 T cells contribute to adenosine production by releasing CD73-containing extracellular vesicles upon activation. These extracellular vesicles have AMPase activity, and the resulting adenosine mediates immune suppression independently of regulatory T cells. In addition, we show that extracellular vesicles isolated from the synovial fluid of patients with juvenile idiopathic arthritis contribute to T cell suppression in a CD73-dependent manner. Our results suggest that the generation of adenosine upon T cell activation is an intrinsic mechanism of human effector T cells that complements regulatory T cell-mediated suppression in the inflamed tissue. Finally, our data underscore the role of immune cell-derived extracellular vesicles in the control of immune responses.
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http://dx.doi.org/10.1038/s41467-021-26134-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501027PMC
October 2021

Induction of IL-22-Producing CD4+ T Cells by Segmented Filamentous Bacteria Independent of Classical Th17 Cells.

Front Immunol 2021 8;12:671331. Epub 2021 Sep 8.

Department of Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.

The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.
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http://dx.doi.org/10.3389/fimmu.2021.671331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456099PMC
October 2021

Landscape of T-cell repertoires with public COVID-19-associated T-cell receptors in pre-pandemic risk cohorts.

Clin Transl Immunology 2021 28;10(9):e1340. Epub 2021 Aug 28.

Department of Internal Medicine IV Oncology/Hematology Martin-Luther-University Halle-Wittenberg Halle (Saale) Germany.

Objectives: T cells have an essential role in the antiviral defence. Public T-cell receptor (TCR) clonotypes are expanded in a substantial proportion of COVID-19 patients. We set out to exploit their potential use as read-out for COVID-19 T-cell immune responses.

Methods: We searched for COVID-19-associated T-cell clones with public TCRs, as defined by identical complementarity-determining region 3 (CDR3) beta chain amino acid sequence that can be reproducibly detected in the blood of COVID-19 patients. Of the different clonotype identification algorithms used in this study, deep sequencing of brain tissue of five patients with fatal COVID-19 delivered 68 TCR clonotypes with superior representation across 140 immune repertoires of unrelated COVID-19 patients.

Results: Mining of immune repertoires from subjects not previously exposed to the virus showed that these clonotypes can be found in almost 20% of pre-pandemic immune repertoires of healthy subjects, with lower representation in repertoires from risk groups like individuals above the age of 60 years or patients with cancer.

Conclusion: Together, our data show that at least a proportion of the SARS-CoV-2 T-cell response is mediated by public TCRs that are present in repertoires of unexposed individuals. The lower representation of these clones in repertoires of risk groups or failure to expand such clones may contribute to more unfavorable clinical COVID-19 courses.
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http://dx.doi.org/10.1002/cti2.1340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401425PMC
August 2021

Functional heterogeneity of CD4 T cells in liver inflammation.

Semin Immunopathol 2021 Aug 31;43(4):549-561. Epub 2021 Aug 31.

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

CD4 T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4 T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4 T cells as a therapeutic target in both NASH and AIH is discussed.
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http://dx.doi.org/10.1007/s00281-021-00881-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443520PMC
August 2021

Efferocytosis fuels malignant pleural effusion through TIMP1.

Sci Adv 2021 08 13;7(33). Epub 2021 Aug 13.

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of and in Mφs or IL-10 receptor in DCs or substantially reduced MPE progression. Our results delineate an inflammatory cascade-from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs-that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE.
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http://dx.doi.org/10.1126/sciadv.abd6734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363144PMC
August 2021

Carbon Monoxide Suppresses Neointima Formation in Transplant Arteriosclerosis by Inhibiting Vascular Progenitor Cell Differentiation.

Arterioscler Thromb Vasc Biol 2021 06 15;41(6):1915-1927. Epub 2021 Apr 15.

Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA (H.S., G.R.L., E.C., D.G., H.W., F.H.B., L.E.O.).

[Figure: see text].
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http://dx.doi.org/10.1161/ATVBAHA.120.315558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159904PMC
June 2021

Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4 T cells in primary sclerosing cholangitis.

J Hepatol 2021 08 24;75(2):414-423. Epub 2021 Mar 24.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg 20246 Germany. Electronic address:

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver.

Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs.

Results: We identified a population of intrahepatic naive-like CD4 T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T17 cells.

Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4 T cells in PSC harbour the propensity to develop into T17 cells.

Lay Summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4 T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.jhep.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310924PMC
August 2021

Clonal expansion and activation of tissue-resident memory-like Th17 cells expressing GM-CSF in the lungs of severe COVID-19 patients.

Sci Immunol 2021 02;6(56)

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Germany.

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 and (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.
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http://dx.doi.org/10.1126/sciimmunol.abf6692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128299PMC
February 2021

Skin-resident innate lymphoid cells converge on a pathogenic effector state.

Nature 2021 04 3;592(7852):128-132. Epub 2021 Feb 3.

Department of Medicine, Sandler Asthma Research Center, University of California San Francisco, San Francisco, CA, USA.

Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines. In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum-even at steady state-reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling.
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http://dx.doi.org/10.1038/s41586-021-03188-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336632PMC
April 2021

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression.

J Hepatol 2021 04 13;74(4):919-930. Epub 2020 Nov 13.

Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

Background & Aims: IL-17A-producing T cells are present in autoimmune cholestatic liver diseases; however, little is known about the contribution of IL-17 to periductal immune responses. Herein, we investigated the role of IL-17 produced by antigen-specific CD8 T cells in a mouse model of cholangitis and in vitro in human cholangiocyte organoids.

Methods: K14-OVAp mice express a major histocompatibility complex I-restricted ovalbumin (OVA) peptide sequence (SIINFEKL) on cholangiocytes. Cholangitis was induced by the adoptive transfer of transgenic OVA-specific ovalbumin transgene (OT)-1 CD8 T cells that either had OT-1 or lacked IL-17A/F (OT-1). The response of mouse and human cholangiocytes/organoids to IL-17A was assessed in vitro.

Results: Transfer of OVA-specific OT-1 cells significantly aggravated periductal inflammation in K14-OVAp recipient mice compared with transfer of OT-1 T cells. OT-1 T cells were highly activated in the liver and displayed increased cytotoxicity and proliferation. IL-17A/F produced by transferred OT-1 CD8 T cells induced upregulation of the inhibitory molecule programmed cell death ligand 1 (PD-L1) on cholangiocytes, restricting cholangitis by limiting cytotoxicity and proliferation of transferred cells. In contrast, OT-1 T cells failed to induce PD-L1 on cholangiocytes, resulting in uncontrolled expansion of cytotoxic CD8 T cells and aggravated cholangitis. Blockade of PD-L1 after transfer of OT-1 T cells with anti-PD-L1 antibody also resulted in aggravated cholangitis. Using human cholangiocyte organoids, we were able to confirm that IL-17A induces PD-L1 expression in cholangiocytes.

Conclusions: We demonstrate that by upregulating PD-L1 on cholangiocytes, IL-17 has an important role in restricting cholangitis and protecting against CD8 T cell-mediated inflammatory bile duct injury. Caution should be exercised when targeting IL-17 for the treatment of cholangitis.

Lay Summary: IL-17 is assumed to be a driver of inflammation in several autoimmune diseases, such as psoriasis. IL-17 is also present in inflammatory diseases of the bile duct, but its role in these conditions is not clear, as the effects of IL-17 depend on the context of its expression. Herein, we investigated the role of IL-17 in an experimental autoimmune cholangitis mouse model, and we identified an important protective effect of IL-17 on cholangiocytes, enabling them to downregulate bile duct inflammation via checkpoint inhibitor PD-L1.
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http://dx.doi.org/10.1016/j.jhep.2020.10.035DOI Listing
April 2021

Pathogen-induced tissue-resident memory T17 (T17) cells amplify autoimmune kidney disease.

Sci Immunol 2020 08;5(50)

III. Department of Medicine, Division of Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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) cells persist in peripheral organs and provide immune protection against reinfection. However, whether T 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 T cells with a T17 signature (termed T17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal T17 cells were induced by pathogens infecting the kidney, such as , , and uropathogenic , and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney T17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced T17 cells have a previously unrecognized function in aggravating autoimmune disease.
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http://dx.doi.org/10.1126/sciimmunol.aba4163DOI Listing
August 2020

The induction and function of the anti-inflammatory fate of T17 cells.

Nat Commun 2020 07 3;11(1):3334. Epub 2020 Jul 3.

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.

T17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of T17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-β signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in T17 cells. Our data thus indicate a key function of T17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of T17 cells with regard to environmental changes.
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http://dx.doi.org/10.1038/s41467-020-17097-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335205PMC
July 2020

IL22BP Mediates the Antitumor Effects of Lymphotoxin Against Colorectal Tumors in Mice and Humans.

Gastroenterology 2020 10 22;159(4):1417-1430.e3. Epub 2020 Jun 22.

Georgia Cancer Center, Augusta University, Augusta, Georgia.

Background & Aims: Unregulated activity of interleukin (IL) 22 promotes intestinal tumorigenesis in mice. IL22 binds the antagonist IL22 subunit alpha 2 (IL22RA2, also called IL22BP). We studied whether alterations in IL22BP contribute to colorectal carcinogenesis in humans and mice.

Methods: We obtained tumor and nontumor tissues from patients with colorectal cancer (CRC) and measured levels of cytokines by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. We measured levels of Il22bp messenger RNA in colon tissues from wild-type, Tnf, Lta, and Ltb mice. Mice were given azoxymethane and dextran sodium sulfate to induce colitis and associated cancer or intracecal injections of MC38 tumor cells. Some mice were given inhibitors of lymphotoxin beta receptor (LTBR). Intestine tissues were analyzed by single-cell sequencing to identify cell sources of lymphotoxin. We performed immunohistochemistry analysis of colon tissue microarrays from patients with CRC (1475 tissue cores, contained tumor and nontumor tissues) and correlated levels of IL22BP with patient survival times.

Results: Levels of IL22BP were decreased in human colorectal tumors, compared with nontumor tissues, and correlated with levels of lymphotoxin. LTBR signaling was required for expression of IL22BP in colon tissues of mice. Wild-type mice given LTBR inhibitors had an increased tumor burden in both models, but LTBR inhibitors did not increase tumor growth in Il22bp mice. Lymphotoxin directly induced expression of IL22BP in cultured human monocyte-derived dendritic cells via activation of nuclear factor κB. Reduced levels of IL22BP in colorectal tumor tissues were associated with shorter survival times of patients with CRC.

Conclusions: Lymphotoxin signaling regulates expression of IL22BP in colon; levels of IL22BP are reduced in human colorectal tumors, associated with shorter survival times. LTBR signaling regulates expression of IL22BP in colon tumors in mice and cultured human dendritic cells. Patients with colorectal tumors that express low levels of IL22BP might benefit from treatment with an IL22 antagonist.
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http://dx.doi.org/10.1053/j.gastro.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607422PMC
October 2020

NK cell receptor NKG2D enforces proinflammatory features and pathogenicity of Th1 and Th17 cells.

J Exp Med 2020 08;217(8)

Innate Immunity, German Rheumatism Research Centre-a Leibniz Institute, Berlin, Germany.

NKG2D is a danger sensor expressed on different subsets of innate and adaptive lymphocytes. Despite its established role as a potent activator of the immune system, NKG2D-driven regulation of CD4+ T helper (Th) cell-mediated immunity remains unclear. In this study, we demonstrate that NKG2D modulates Th1 and proinflammatory T-bet+ Th17 cell effector functions in vitro and in vivo. In particular, NKG2D promotes higher production of proinflammatory cytokines by Th1 and T-bet+ Th17 cells and reinforces their transcription of type 1 signature genes, including Tbx21. Conditional deletion of NKG2D in T cells impairs the ability of antigen-specific CD4+ T cells to promote inflammation in vivo during antigen-induced arthritis and experimental autoimmune encephalomyelitis, indicating that NKG2D is an important target for the amelioration of Th1- and Th17-mediated chronic inflammatory diseases.
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http://dx.doi.org/10.1084/jem.20190133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398170PMC
August 2020

TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer.

Nat Commun 2020 05 25;11(1):2608. Epub 2020 May 25.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.

IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-β1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-β signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-β1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-β signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-β signaling. We show that TGF-β, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.
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http://dx.doi.org/10.1038/s41467-020-16363-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248087PMC
May 2020

Systemic interleukin 10 levels indicate advanced stages while interleukin 17A levels correlate with reduced survival in esophageal adenocarcinomas.

PLoS One 2020 16;15(4):e0231833. Epub 2020 Apr 16.

Section of Molecular Immunology und Gastroenterology, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Introduction: Reflux promotes esophageal adenocarcinomas (EAC) creating a chronic inflammatory environment. EAC show an increasing incidence in the Western World and median survival rates are still low. The main reasons for poor prognosis despite new multimodal therapies are diagnosis of EACs at an already advanced stage and distant metastases. Hence, we wanted to investigate the presence of systemic inflammatory interleukins (IL) and their impact on patient prognosis.

Material And Methods: Systemic expression levels of pro- and anti-inflammatory markers (IL-2, IL-4, IL-6, IL-10, IL-17A and IL-22) in the sera of 43 EAC patients without neoadjuvant radiochemotherapy were measured by flow cytometric analysis. A correlation to clinicopathological data was performed. Log-rank and Cox regression analysis were used to investigate the impact on patient survival. 43 sera of age and gender matched healthy volunteers were used as controls.

Results: Increased systemic IL-6 (p = 0.044) and lower IL-17A (p = 0.002) levels were found in EAC patients as opposed to controls. A correlation of IL-10 levels with an increased T stage was found (p = 0.020). Also, systemic IL-10 levels were highly elevated in patients with distant metastasis (p<0.001). However, only systemic IL-17A levels had an influence on patient survival in multivariate analysis.

Conclusion: Systemic IL-6 levels are increased, while IL-17A levels are reduced in EAC patients compared to healthy controls. In addition, circulating IL-10 might help to identify patients with advanced disease and high IL-17A might indicate a limited prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231833PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162521PMC
August 2020

Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival.

Cancer Immunol Immunother 2020 Jun 25;69(6):1043-1056. Epub 2020 Feb 25.

Section of Molecular Immunology and Gastroenterology, Center of Internal Medicine, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.

Objective: Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood.

Methods: mRNA expression levels of pro- and anti-inflammatory markers in 39 EAC patients without neoadjuvant radio-chemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry.

Results: Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4 T cells with a reduction in CD4 T cells producing IL-22 or IL-17A. We also observed an increase in CD4CD127FOXP3 cells producing IL-10. Accumulation of FOXP3 T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis.

Conclusion: EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.
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http://dx.doi.org/10.1007/s00262-020-02517-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230052PMC
June 2020

Helminth Infections Suppress the Efficacy of Vaccination against Seasonal Influenza.

Cell Rep 2019 Nov;29(8):2243-2256.e4

Section for Molecular Biology and Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany. Electronic address:

Helminth parasites infect more than a quarter of the human population and inflict significant changes to the immunological status of their hosts. Here, we analyze the impact of helminth infections on the efficacy of vaccinations using Litomosoides sigmodontis-infected mice. Concurrent helminth infection reduces the quantity and quality of antibody responses to vaccination against seasonal influenza. Vaccination-induced protection against challenge infections with the human pathogenic 2009 pandemic H1N1 influenza A virus is drastically impaired in helminth-infected mice. Impaired responses are also observed if vaccinations are performed after clearance of a previous helminth infection, suggesting that individuals in helminth-endemic areas may not always benefit from vaccinations, even in the absence of an acute and diagnosable helminth infection. Mechanistically, the suppression is associated with a systemic and sustained expansion of interleukin (IL)-10-producing CD4CD49LAG-3 type 1 regulatory T cells and partially abrogated by in vivo blockade of the IL-10 receptor.
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http://dx.doi.org/10.1016/j.celrep.2019.10.051DOI Listing
November 2019

Title: IL-10-producing T cells and their dual functions.

Semin Immunol 2019 08 14;44:101335. Epub 2019 Nov 14.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address:

Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, which significantly contributes to the maintenance and reestablishment of immune homeostasis. However, this classical view fails to fully describe the pleiotropic roles of IL-10. Indeed, IL-10 can also promote immune responses, e.g. by supporting B-cell and CD8 T-cell activation. The reasons for these seemingly opposing functions are unclear to a large extent. Recent and previous studies suggest that the cellular source and the microenvironment impact the function of IL-10. However, studies addressing the mechanisms which determine whether IL-10 promotes inflammation or controls it have just begun. This review first summarizes the recent findings on the heterogeneity of IL-10 producing T cells and their impact on the target cells. Finally, we will propose two possible explanations for the dual functions of IL-10.
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http://dx.doi.org/10.1016/j.smim.2019.101335DOI Listing
August 2019

Effector T17 Cells Give Rise to Long-Lived T Cells that Are Essential for an Immediate Response against Bacterial Infection.

Cell 2019 08;178(5):1176-1188.e15

Department of Immunobiology, School of Medicine, Yale University, New Haven, CT, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA. Electronic address:

Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (T) cells. However, the cellular origin of CD4 T cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 T cells derive from IL-17A-producing effector (T17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exT17 T cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, γδ T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exT17 T cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 T cells during bacterial infection, offering novel strategies for targeted vaccine design.
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http://dx.doi.org/10.1016/j.cell.2019.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057720PMC
August 2019

Conserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification.

Nat Commun 2019 06 28;10(1):2892. Epub 2019 Jun 28.

Immunology and Allergy Unit, Department of Medicine, Solna, Karolinska Institute and University Hospital, 17176, Stockholm, Sweden.

Clinical manifestations and response to therapies in ulcerative colitis (UC) are heterogeneous, yet patient classification criteria for tailored therapies are currently lacking. Here, we present an unsupervised molecular classification of UC patients, concordant with response to therapy in independent retrospective cohorts. We show that classical clustering of UC patient tissue transcriptomic data sets does not identify clinically relevant profiles, likely due to associated covariates. To overcome this, we compare cross-sectional human data sets with a newly generated longitudinal transcriptome profile of murine DSS-induced colitis. We show that the majority of colitis risk-associated gene expression peaks during the inflammatory rather than the recovery phase. Moreover, we achieve UC patient clustering into two distinct transcriptomic profiles, differing in neutrophil-related gene activation. Notably, 87% of patients in UC1 cluster are unresponsive to two most widely used biological therapies. These results demonstrate that cross-species comparison enables stratification of patients undistinguishable by other molecular approaches.
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http://dx.doi.org/10.1038/s41467-019-10769-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598981PMC
June 2019

Role of IL-10 Receptor Signaling in the Function of CD4+ T-Regulatory Type 1 cells: T-Cell Therapy in Patients with Inflammatory Bowel Disease.

Crit Rev Immunol 2018 ;38(5):415-431

Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

Inflammatory bowel disease (IBD) is caused by the interplay of various factors. It occurs in genetically susceptible people due to dysregulated immune responses to several unknown antigens, including those derived from the commensal microbiota. Effector T-helper cells, especially TH17 cells, are considered a major driver of disease progression. The endogenous resident counterparts of effector T-helper cells are the regulatory T cells, mainly Foxp3+ Treg cells and type 1 regulatory (TR1) T cells. Both have strong immune regulatory capacity and can terminate immune responses. Interestingly, the expression of IL-10 receptor on regulatory T cells has a high impact on the regulatory capacity of these cells. Inflammatory bowel disease is becoming a global health issue. No curative therapy is currently available. However, initial clinical trials have been conducted successfully, proving the safety of a regulatory T-cell-based therapy. This therapy might lead to long-lasting remission and to a possible cure for IBD. This review provides a summary of the current findings and the outcome of the clinical trials based on T-cell therapy for IBD and for other inflammatory conditions.
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http://dx.doi.org/10.1615/CritRevImmunol.2018026850DOI Listing
September 2019

Human Fetal TNF-α-Cytokine-Producing CD4 Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life.

Immunity 2019 02 12;50(2):462-476.e8. Epub 2019 Feb 12.

Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany. Electronic address:

Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)CD4CD69 T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4 T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4 T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4 Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4 T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.
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http://dx.doi.org/10.1016/j.immuni.2018.12.010DOI Listing
February 2019

Dietary Habits and Intestinal Immunity: From Food Intake to CD4 T Cells.

Front Immunol 2018 15;9:3177. Epub 2019 Jan 15.

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Dietary habits have a profound impact on intestinal homeostasis and in general on human health. In Western countries, high intake of calories derived from fried products, butter and processed meat is favored over dietary regimens rich in fruits and vegetables. This type of diet is usually referred to as Western-type diet (WTD) and it has been associated with several metabolic and chronic inflammatory conditions of the gastrointestinal tract. In this review, we describe how WTD promotes intestinal and extra-intestinal inflammation and alters mucosal immunity acting on CD4 T cells in a microbiota-dependent or -independent fashion, ultimately leading to higher susceptibility to infectious and autoimmune diseases. Moreover, summarizing recent findings, we propose how dietary supplementation with fiber and vitamins could be used as a tool to modulate CD4 T cell phenotype and function, ameliorating inflammation and restoring mucosal homeostasis.
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http://dx.doi.org/10.3389/fimmu.2018.03177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340974PMC
October 2019

Molecular and functional heterogeneity of IL-10-producing CD4 T cells.

Nat Commun 2018 12 21;9(1):5457. Epub 2018 Dec 21.

I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.

IL-10 is a prototypical anti-inflammatory cytokine, which is fundamental to the maintenance of immune homeostasis, especially in the intestine. There is an assumption that cells producing IL-10 have an immunoregulatory function. However, here we report that IL-10-producing CD4 T cells are phenotypically and functionally heterogeneous. By combining single cell transcriptome and functional analyses, we identified a subpopulation of IL-10-producing Foxp3 CD4 T cells that displays regulatory activity unlike other IL-10-producing CD4 T cells, which are unexpectedly pro-inflammatory. The combinatorial expression of co-inhibitory receptors is sufficient to discriminate IL-10-producing CD4 T cells with regulatory function from others and to identify them across different tissues and disease models in mice and humans. These regulatory IL-10-producing Foxp3 CD4 T cells have a unique transcriptional program, which goes beyond the regulation of IL-10 expression. Finally, we found that patients with Inflammatory Bowel Disease demonstrate a deficiency in this specific regulatory T-cell subpopulation.
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http://dx.doi.org/10.1038/s41467-018-07581-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303294PMC
December 2018

The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases.

Immunity 2018 12;49(6):1004-1019

Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden.

Thirty years ago, one of the first types of CD4 T regulatory cells was discovered and named T regulatory type 1 (Tr1) cells. Tr1 cells represent a distinct population of T cells, which are induced in the periphery upon antigen exposure under tolerogenic conditions. They produce the immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), do not constitutively express FOXP3, and suppress the function of effector immune cells. In this review, the key studies leading to the identification and biological characterization of Tr1 cells are recapitulated. The fundamental role of Tr1 cells in regulating immune responses to pathogenic and non-pathogenic antigens, as well as their use as cell therapeutics, is summarized.
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http://dx.doi.org/10.1016/j.immuni.2018.12.001DOI Listing
December 2018

Commensal Bacteria-Specific CD4 T Cell Responses in Health and Disease.

Front Immunol 2018 20;9:2667. Epub 2018 Nov 20.

Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.

Over the course of evolution, mammalian body surfaces have adapted their complex immune system to allow a harmless coexistence with the commensal microbiota. The adaptive immune response, in particular CD4 T cell-mediated, is crucial to maintain intestinal immune homeostasis by discriminating between harmless (e.g., dietary compounds and intestinal microbes) and harmful stimuli (e.g., pathogens). To tolerate food molecules and microbial components, CD4 T cells establish a finely tuned crosstalk with the environment whereas breakdown of these mechanisms might lead to chronic disease associated with mucosal barriers and beyond. How commensal-specific immune responses are regulated and how these molecular and cellular mechanisms can be manipulated to treat chronic disorders is yet poorly understood. In this review, we discuss current knowledge of the regulation of commensal bacteria-specific CD4 T cells. We place particular focus on the key role of commensal-specific CD4 T cells in maintaining tolerance while efficiently eradicating local and systemic infections, with a focus on factors that trigger their aberrant activation.
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http://dx.doi.org/10.3389/fimmu.2018.02667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256970PMC
October 2019

Author Correction: Differential expression pattern of co-inhibitory molecules on CD4 T cells in uncomplicated versus complicated malaria.

Sci Rep 2018 Nov 29;8(1):17587. Epub 2018 Nov 29.

I. Medical Department, Division of Tropical Medicine and Infectious Diseases, University Medical Centre Hamburg Eppendorf, 20246, Hamburg, Germany.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-36410-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261966PMC
November 2018

Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3 Regulatory T Cells.

J Immunol 2018 12 16;201(12):3558-3568. Epub 2018 Nov 16.

I. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany;

Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3 regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell-mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation.
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http://dx.doi.org/10.4049/jimmunol.1800711DOI Listing
December 2018
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