Publications by authors named "Katharina Zoldan"

11 Publications

  • Page 1 of 1

Rapid and stable mobilization of CD8 T cells by SARS-CoV-2 mRNA vaccine.

Nature 2021 09 28;597(7875):268-273. Epub 2021 Jul 28.

Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

SARS-CoV-2 spike mRNA vaccines mediate protection from severe disease as early as ten days after prime vaccination, when neutralizing antibodies are hardly detectable. Vaccine-induced CD8 T cells may therefore be the main mediators of protection at this early stage. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8 T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4 T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8 T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8 T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.
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http://dx.doi.org/10.1038/s41586-021-03841-4DOI Listing
September 2021

Blood reelin in the progression of chronic liver disease.

Adv Med Sci 2021 Mar 6;66(1):148-154. Epub 2021 Feb 6.

Department of Medicine II, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Purpose: Reelin is an extracellular matrix protein originally found to be associated with neuropsychiatric disorders. Recent findings indicate, that reelin may also play an important role in the process of liver fibrosis as well as in the development of hepatocellular carcinoma (HCC). Against this background, the aim of our study was to explore alterations in blood reelin levels in different stages of chronic liver diseases.

Patients And Methods: We analyzed blood samples of patients with chronic liver disease without liver fibrosis (n ​= ​25), with liver fibrosis (n ​= ​36), with liver cirrhosis (n ​= ​74), with HCC (n ​= ​26) as well as of healthy controls (n ​= ​15). Blood reelin concentrations were determined utilizing an enzyme-linked immunosorbent assay.

Results: Blood reelin levels were significantly elevated in patients who had liver fibrosis or cirrhosis compared to patients without liver fibrosis and healthy controls (13.9 (10.2-21.1) ng/ml vs. 11.2 (8.8-16.8) ng/ml, p ​= ​0.032). Importantly, patients with HCC displayed significantly higher reelin concentrations compared to patients with liver cirrhosis alone (27.0 (17.3-35.9) ng/ml vs. 16.6 (11.0-22.7) ng/ml, p ​< ​0.001). Blood reelin was not relevantly linked to liver function, inflammation and etiology of liver disease.

Conclusions: Our results demonstrate, that blood reelin levels are altered in different stages of chronic liver disease, which makes reelin a potential biomarker in this setting. This may be especially relevant with regard to its use as an additional tumor marker of HCC.
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http://dx.doi.org/10.1016/j.advms.2021.01.006DOI Listing
March 2021

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis.

J Hepatol 2021 03 24;74(3):649-660. Epub 2020 Oct 24.

Department of Medicine II, Medical Center - University of Freiburg, Germany; Faculty of Medicine, University of Freiburg, Germany; Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Germany. Electronic address:

Background & Aims: Patients with decompensated cirrhosis suffer from recurrent infections and inadequate responses to prophylactic vaccinations. However, many patients present with hypergammaglobulinemia (HGG), indicating a sustained ability to generate antibody responses. As follicular T helper (Tfh) cells are central facilitators of humoral immunity, we hypothesized that Tfh cell responses may be altered in advanced liver disease and we aimed to identify the mechanisms underlying any such alterations.

Methods: Tfh, regulatory T (Treg) cells, B cells, circulating cytokines and immunoglobulins were analyzed in cohorts of patients with compensated (n = 37) and decompensated cirrhosis (n = 82) and in non-cirrhotic controls (n = 45). Intrahepatic T cells were analyzed in 8 decompensated patients. The influence of IL-2 on Tfh cell function was evaluated in vitro, including Tfh cell cloning and T cell-B cell co-cultures with clones and primary tonsil-derived Tfh cells.

Results: Tfh cell frequencies were reduced in patients with decompensated cirrhosis, with phenotypic signatures indicative of increased IL-2 signaling. Soluble IL-2 receptor (sCD25) was elevated in these patients and CD4 T cells were more responsive to IL-2 signaling, as characterized by STAT5 phosphorylation. IL-2 exposure in vitro diminished the Tfh phenotype and resulted in impaired Tfh helper function in co-culture experiments with naïve B cells. Tfh cells were barely detectable in cirrhotic livers. IL-2 signatures on Tfh cells in decompensated patients correlated with immunoglobulin levels, which were found to be associated with improved survival.

Conclusions: Tfh cell impairment represents a previously underestimated feature of cirrhosis-associated immune dysfunction that is driven by IL-2. The presence of HGG in decompensated patients predicts an intact Tfh cell compartment and is associated with a favorable outcome.

Lay Summary: Patients with advanced cirrhosis often fail to generate protective immunity after prophylactic vaccinations and suffer from recurring infections that are associated with high mortality. Follicular T helper (Tfh) cells are specialized CD4 T cells that enable the emergence of antibody responses against microbial pathogens. This report demonstrates that Tfh cells are impaired in patients with advanced cirrhosis due to interleukin-2 signaling, a cytokine that is known to impair the generation of Tfh cells.
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http://dx.doi.org/10.1016/j.jhep.2020.10.012DOI Listing
March 2021

Ustekinumab Inhibits T Follicular Helper Cell Differentiation in Patients With Crohn's Disease.

Cell Mol Gastroenterol Hepatol 2021 15;11(1):1-12. Epub 2020 Jul 15.

Department of Medicine II, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background & Aims: The pathogenesis of chronic inflammatory bowel diseases (Crohn's disease [CD] and ulcerative colitis) involves dysregulated TH1 and TH17 cell responses, which can be targeted therapeutically by the monoclonal antibody Ustekinumab directed against the joint p40 subunit of IL-12 and IL-23. These cytokines may also regulate the differentiation of T follicular helper (TFH) cells, which promote B cell function in germinal centers. However, the role of TFH cells in CD pathogenesis and impact of Ustekinumab therapy on TFH cell fate in patients are poorly defined.

Methods: Lymphocytes were isolated from peripheral blood (n=45) and intestinal biopsies (n=15) of CD patients or healthy controls (n=21) and analyzed by flow cytometry to assess TFH cell phenotypes and functions ex vivo. In addition, TFH cell differentiation was analyzed in the presence of Ustekinumab in vitro.

Results: TFH cell frequencies in the intestine as well as peripheral blood were associated with endoscopic as well as biochemical evidence of CD activity. CD patients with clinical response to Ustekinumab, but not those with response to anti-TNF antibodies, displayed reduced frequencies of circulating TFH cells in a concentration-dependent manner while the TFH phenotype was not affected by Ustekinumab therapy. In keeping with this notion, TFH cell differentiation was inhibited by Ustekinumab in vitro while TFH cell maintenance was not affected. Moreover, Ustekinumab therapy resulted in reduced germinal center activity in CD patients in vivo.

Conclusions: These data implicate TFH cells in the pathogenesis of CD and indicate that Ustekinumab therapy affects TFH cell differentiation, which may influence TFH-mediated immune functions in UST-treated CD patients.
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http://dx.doi.org/10.1016/j.jcmgh.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593584PMC
July 2020

B protected: from vertical HCV transmission?

Gut 2020 12 30;69(12):2061-2062. Epub 2020 Jun 30.

Department of Medicine II, University Hospital Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

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http://dx.doi.org/10.1136/gutjnl-2020-321364DOI Listing
December 2020

Exhausted phenotype of follicular CD8 T cells in CVID.

J Allergy Clin Immunol 2020 10 10;146(4):912-915.e13. Epub 2020 Mar 10.

Divison of Immunodeficiency, Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.02.025DOI Listing
October 2020

Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination.

J Clin Invest 2020 02;130(2):998-1009

Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.

BACKGROUNDChronic hepatitis C virus (HCV) infection is characterized by a severe impairment of HCV-specific CD4+ T cell help that is driven by chronic antigen stimulation. We aimed to study the fate of HCV-specific CD4+ T cells after virus elimination.METHODSHCV-specific CD4+ T cell responses were longitudinally analyzed using MHC class II tetramer technology, multicolor flow cytometry, and RNA sequencing in a cohort of patients chronically infected with HCV undergoing therapy with direct-acting antivirals. In addition, HCV-specific neutralizing antibodies and CXCL13 levels were analyzed.RESULTSWe observed that the frequency of HCV-specific CD4+ T cells increased within 2 weeks after initiating direct-acting antiviral therapy. Multicolor flow cytometry revealed a downregulation of exhaustion and activation markers and an upregulation of memory-associated markers. Although cells with a Th1 phenotype were the predominant subset at baseline, cells with phenotypic and transcriptional characteristics of follicular T helper cells increasingly shaped the circulating HCV-specific CD4+ T cell repertoire, suggesting antigen-independent survival of this subset. These changes were accompanied by a decline of HCV-specific neutralizing antibodies and the germinal center activity.CONCLUSIONWe identified a population of HCV-specific CD4+ T cells with a follicular T helper cell signature that is maintained after therapy-induced elimination of persistent infection and may constitute an important target population for vaccination efforts to prevent reinfection and immunotherapeutic approaches for persistent viral infections.FUNDINGDeutsche Forschungsgemeinschaft (DFG, German Research Foundation), the National Institute of Allergy and Infectious Diseases (NIAID), the European Union, the Berta-Ottenstein-Programme for Advanced Clinician Scientists, and the ANRS.
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http://dx.doi.org/10.1172/JCI129642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994124PMC
February 2020

OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection.

J Hepatol 2019 06 28;70(6):1103-1113. Epub 2019 Feb 28.

Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany. Electronic address:

Background & Aims: Current antiviral therapies lack the potential to eliminate persistent hepatitis B virus (HBV) infection. HBV-specific T cells are crucial for HBV control and have recently been shown to be protective in patients following discontinuation of antiviral therapy. Thus, T cell-based approaches may greatly improve the therapeutic landscape of HBV infection. We aimed to augment HBV-specific CD4 T cells from chronically infected patients by targeting different immunological pathways.

Methods: Expression of various co-stimulatory and inhibitory receptors on HBV- and influenza-specific CD4 T cells was analyzed directly ex vivo by MHC class II-tetramers. Patients infected with HBV genotype D were screened for CD4 T cell responses by IFN-γ ELISpot and intracellular cytokine staining following stimulation with overlapping peptides (OLPs) spanning the HBV-polyprotein. Stimulation with recombinant IL-7, an agonistic OX40-antibody or blockade of PD-L1 was performed in antigen-specific in vitro cultures. Cytokine secretion and expression of transcription factors were analyzed by flow cytometry. Responses targeting influenza, Epstein-Barr virus and tetanus toxoid served as controls.

Results: Tetramer-staining revealed that the IL-7 receptor-alpha (CD127), OX40 and PD-1 constitute possible therapeutic targets as they were all strongly expressed on HBV-specific CD4 T cells ex vivo. The HBV-specific CD4 T cell responses identified by OLP screening targeted predominantly the HBV-polymerase and core proteins. Combined OX40 stimulation and PD-L1 blockade significantly augmented IFN-γ and IL-21 producing HBV-specific CD4 T cells in vitro, suggesting active T helper type 1 cell and follicular T helper cell programs. Indeed, transcription factors T-bet and Bcl6 were strongly expressed in cytokine-producing cells.

Conclusions: Combined OX40 stimulation and PD-L1 blockade augmented secretion of the helper T cell signature cytokines IFN-γ and IL-21, suggesting that immunotherapeutic approaches can improve HBV-specific CD4 T cell responses.

Lay Summary: CD4 T cells are important in controlling viral infections but are impaired in the context of chronic hepatitis B virus (HBV) infection. Therapeutic approaches to cure chronic HBV infection are highly likely to require an immune-stimulatory component. This study demonstrates that HBV-specific CD4 T cells can be functionally augmented by combined stimulation of the co-stimulatory molecule OX40 and blockade of the inhibitory PD-1 pathway.
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http://dx.doi.org/10.1016/j.jhep.2019.02.016DOI Listing
June 2019

Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis.

Hepatol Commun 2018 Sep 7;2(9):1051-1063. Epub 2018 Sep 7.

Department of Medicine II, University Medical Cewnter, Faculty of Medicine University of Freiburg Freiburg Germany.

Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common cholestatic liver diseases. While PBC is generally accepted to be an autoimmune disorder characterized by pathognomonic autoantibodies against mitochondrial antigens, the pathogenesis of PSC is less precisely defined; however, some degree of altered immunity toward autoantigens has been suggested. Follicular T helper (Tfh) cells, a distinct clusters of differentiation (CD)4 T-cell subset specialized in facilitating antibody responses, have been shown to contribute to humoral autoimmunity in various disorders; yet, there is only limited information on possible alterations of Tfh cells in the context of cholestatic liver diseases. Thus, we addressed this important question by analyzing the frequency, activation status, and function of Tfh cells and frequencies of regulatory follicular T helper (Tfr) cells in well-defined cohorts of patients with PBC and patients with PSC. Interestingly, we observed a significant increase in circulating chemokine (C-X-C motif) receptor 5 (CXCR5)+programmed death 1 (PD-1) +CD4+ Tfh cells in patients with PBC but not in those with PSC. Although the frequency of potentially pathogenic chemokine (C-C motif) receptor 7 (CCR7)lowCXCR5+PD-1+CD4+ Tfh cells was increased in both disorders compared to healthy donors, the increase was significantly more pronounced in PBC. Furthermore, in patients with PBC, Tfh cells displayed stronger expression of the activation markers OX40 and inducible costimulator of T cells, correlated with anti-anti-mitochondrial antibody M2 and immunoglobulin M titers, and were most significantly increased in patients with cirrhosis. Tfr cell numbers were similarly increased; however, Tfh/Tfr ratios were unaltered in PSC and PBC. These alterations did not correlate with increased secretion of the Tfh signature cytokine interleukin-21 in sorted CD4 T cells. : Significant alterations occur in the Tfh cell compartment in cholestatic liver diseases, suggesting that Tfh cells influence the pathogenesis of PBC and to a lesser extend PSC.
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http://dx.doi.org/10.1002/hep4.1226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128229PMC
September 2018

Benzo(a)pyrene attenuates the pattern-recognition-receptor induced proinflammatory phenotype of murine macrophages by inducing IL-10 expression in an aryl hydrocarbon receptor-dependent manner.

Toxicology 2018 11 24;409:80-90. Epub 2018 Jul 24.

Department of Therapy Validation, Fraunhofer Institute for Cell Therapy and Immunology, 04103 Leipzig, Germany. Electronic address:

Polycyclic aromatic hydrocarbons such as benzo(a)pyrene (BaP) are environmental contaminants known to be immunosuppressive. Most effects of BaP towards immune cells are thought to be mediated through activation of the aryl hydrocarbon receptor (AhR). The AhR is a ligand-activated transcription factor, which plays a critical modulatory role in various cells during immune response. Macrophages are key players in innate immunity against intracellular bacteria and are discussed to be a target of AhR-mediated immune regulation. However, so far there is only incomplete knowledge about the effects of BaP on activated macrophages and whether these effects are AhR-dependent in each case. Using murine bone marrow-derived macrophages (BMMs) stimulated with heat-killed salmonellae as a source of different pathogen-associated molecular patterns (PAMPs) for stimulation of different pattern recognition receptors (PRRs) as an in-vitro model, we studied the immunomodulatory effects of low-dose BaP exposure. PRR-activated BMMs produced nitric oxide (NO) and a spectrum of proinflammatory cytokines, i.e. tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-12 but also the anti-inflammatory cytokine IL-10. While BaP exposure suppressed the production of proinflammatory cytokines, the secretion of IL-10 was augmented. Moreover, BaP exposure increased the expression of major histocompatibility complex class II (MHC-II), CD14, Fcγ receptor I (FcγRI/CD64), or CD86, enhanced NO production and phagocytosis what may be beneficial for phagocytosis and killing of microbial pathogens. Of note, without PRR activation low-dose BaP exposure has little influence on the macrophage phenotype. BMMs from AhR-deficient (Ahr) mice were widely refractory to BaP-induced modulation of cytokine production, surface marker expression, and functional properties in response to PAMPs stimulation, indicating that these effects are dependent on AhR. In summary, these data suggest that induction of AhR-mediated signalling pathways by BaP may attenuate the proinflammatory phenotype of PRR-activated BMMs, while activating IL-10-mediated anti-inflammatory properties but also enhancing uptake and killing of pathogens as well as antigen presentation. Together these features imply a favourable role of BaP exposure for macrophage functions in an ongoing immune response. However, the strong induction of IL-10 may lead to defective pathogen clearance and subsequently to chronic persistent infection. This concept suggests an inhibitory rather than a supporting influence of environmental BaP on immunity to infection or cancer and also emphasises the important regulatory role of AhR in immunity and inflammation.
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http://dx.doi.org/10.1016/j.tox.2018.07.011DOI Listing
November 2018

Increase of CD25 expression on bovine neutrophils correlates with disease severity in post-partum and early lactating dairy cows.

Dev Comp Immunol 2014 Dec 11;47(2):254-63. Epub 2014 Aug 11.

Department of Cell Engineering, Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany. Electronic address:

Polymorph-nuclear neutrophils (PMN) in cattle exhibit unique features when compared to human or murine PMN and are of particular interest concerning the risk of post-partum mammary gland or extra-mammary infections related to the periparturient suppression of neutrophil functions. Former studies could show that effects of IL-2 on innate immune cells such as PMN were mediated by the interleukin-2 receptor (IL-2R) β and γ chains. In the current study we could detect IL-2Rα (CD25) expression on bovine PMN using flow-cytometric analysis. CD25 was detected on granulocytes from post-partum and early lactating cows with different inflammatory conditions. The expression of CD25 on PMN in blood and raw milk increased with disease severity. Our results suggest CD25 expression on PMN as a potential biomarker for acute infections in cattle. Furthermore, our data provide a basis to better understanding of the periparturient functional suppressions of PMN that might reveal new molecular targets for therapy or prevention of disease.
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http://dx.doi.org/10.1016/j.dci.2014.08.002DOI Listing
December 2014
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