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TRANSLATIONAL EXPERIMENTAL IMMUNOLOGY LAB

Group of Bertram Bengsch

Prof. Dr. Dr. Bertram Bengsch (Group leader)

+49 (0) 761 270-32870

Dr. Maryam Barsch (Clinician Scientist)

+49 (0) 761 270-34010

Dr. Jürgen Beck (PostDoc)

+49 (0) 761 270-36330

Ira Godbole (PhD student)

+49 (0) 761 270-35110

Laurenz Krimmel (MD student) 

 

Ke Meng (PhD student)

+49 (0) 761 270-35110

Dr. Julia Mitschke (PostDoc) 

+49 (0) 761 270-33290

Patricia Otto-Mora (MTA)

+49 (0) 761 270-35090

Dr. Günter Päth (Post Doc)

+49 (0) 761 270-33290

Felix Röttele (PhD student) 

+49 (0) 761/270-33962

Henrike Salié (MD student)

 

Lea Seidel-Raub (PhD student)

 

Emilia Schlaak (MD student)

 

Jonas Stritzker (MD student)

 

Yuan Suo (PhD student)

+49 (0) 761 270-35110

Nandini Terway (PhD student)

+49 (0) 761 270-33960

Dr. Frances Winkler (PostDoc)

+49 (0) 761 270-33961

Lara Wischer (MD student)

 

Weimeng Yu (PhD student)

+49 (0) 761 270-33960

 

Open positions

We are seeking a highly motivated individual with a passion for exciting state-of-the art technology to work with a team of translational immunologists to lead the mass cytometry and imaging facility in the Bengsch lab as part of the Translational EXperimental IMmunology labs at the University of Freiburg, Germany.

Key Responsibilities:

  • operation, maintenance and use of the CyTOF Helios and the HyperionImaging System
  • build and optimize mass cytometry and imaging cytometry antibody panels
  • conjugation and QC of mass cytometry reagents
  • consult with users regarding potential mass cytometry projects which may include guiding experimental set-up and procedure optimization, panel design, and data analysis consultation
  • basic data quality assessment
  • perform and analyze mass cytometry and imaging experiments
  • act as a liaison between users and applications specialist


Key Requirements:

  • PhD degree in immunology, biological sciences, biochemistry or related field (other technical and academic (diploma/Master’s) degrees will be considered based on research experience)
  • demonstrated skill with flow or mass cytometry (previous experience with mass cytometry is a plus) (sample preparation, instrument optimization and data analysis)
  • experience with Immunofluorescence and/or Immunohistochemistry techniques or Imaging Mass cytometry (slide preparation staining optimization visualization and data analysis).
  • interest in bioinformatics, experience with basic flow cytometry software and R preferred
  • ability to identify and troubleshoot critical issues
  • detail-oriented
  • excellent communication and organizational skills


What we offer:

  • exciting translational research
  • work in an interdisciplinary team
  • being part of the German Mass Cytometry Network
  • hospital-standard social benefits, e.g., UKF job ticket
  • employment according to TV-L according to academic qualification
  • Freiburg is an attractive University city next to the Black Forest in Germany, that is also highly international, "green" and also considered a top destination close to France and Switzerland surrounded by a beautiful landscape


Please direct your informative applications with CV and letter of motivation to masscytometry.med2@uniklinik-freiburg.de or contact Bertram Bengsch (PI) directly.

Translational Systems Immunology in Hepatogastroenterology

The immune system is key to the understanding of many infectious, autoimmune and malignant diseases. In the lab, we study how the immune system responds to these challenges with the goal to translate this better understanding to inform therapeutic decisions, such as during immunotherapy, and identify cellular mechanisms controlling immune function to reveal additional targets for the manipulation of immune responses. We utilize advanced single-cell profiling approaches including mass cytometry and imaging mass cytometry in combination with algorithmic deconvolution of the dense data sets.

Diseases currently studied in the lab:

  • Acute and chronic viral hepatitis (focus on HBV and HCV infection)
  • COVID19
  • Inflammatory Bowel disease
  • Hepatocellular Carcinoma
  • Non-alcoholic Steatohepatitis
  • Autoimmune Hepatitis
  • Checkpoint-Blockade - associated adverse immune hepatitis and enteritis
  • Malignant Melanoma


A major focus in the lab is centered on understanding exhausted T cells (TEX), which constitute a T cell lineage distinct from functional memory and effector cells that is characterized by co-expression of immunoregulatory molecules, an altered transcriptional and epigenetic landscape and reduced effector and memory functionality. We have demonstrated that bioenergetic regulation through immune checkpoints (e.g., PD-1) is an important driver of exhaustion. Further, we have demonstrated heterogeneity and disease associations of different varieties of exhausted T cells in humans that are impacted by therapy. Ongoing projects currently focus on understanding the cellular mechanisms underlying the differential usage of immunometabolism in different subtypes of T cells and understanding the role of peripheral and tissue-resident immune populations.

We work closely together with the Freiburg Liver Immunology research groups. Our lab runs the Freiburg Mass Cytometry Unit.

Funding

  • Sonderforschungsbereich-TRR179 (Deutsche Forschungsgemeinschaft, DFG)
  • Sonderforschungsbereich 1160: IMPATH (Deutsche Forschungsgemeinschaft, DFG)
  • Exzellenzcluster BIOSS und CIBSS (Centre for integrative Signaling Studies) 
  • German Mass Cytometry Network (GERMANET)

Group of Tobias Böttler

Prof. Dr. Tobias Böttler (Group leader)  

+49 (0) 761/270-34043

Dr. Rafael Käser (Clinician scientist)

+49 (0) 761/270-35500

Carolin Heni (MD student)

+49 (0) 761/270-35110

Lara Kelsch (PhD student)

+49 (0) 761/270-35110

Stefan Marinescu (MD Student)

 

Jill Werner (PhD student)

+49 (0) 761/270-35110

Katharina Baumeister (PostDoc)

 

Research interest

Immune responses to viral pathogens are tightly regulated. During acute viral infections, a strong and multi-specific T cell response is required to control and eliminate the pathogen. Subsequently, the majority of T cells undergo apoptosis, to protect the host from immune mediated damage, and a small subset of cells turn into pathogen-specific memory cells. The processes that mediate T cell expansion, contraction and survival are strongly influenced by various co-stimulatory molecules. Unfortunately, viruses such as Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV) have the ability to establish persistence and in such cases, T cells are often functionally impaired or entirely lost. However, the signals that regulate T cell survival and function in chronic viral hepatitis are incompletely understood. We are interested in the characterization of these signals in the context of acute and chronic viral hepatitis B, C and E with a particular focus on the role of co-stimulatory molecules and virus-specific CD4 T cells. In addition, T cell responses to viruses and vaccinations are severaly impaired in the context of chronic liver disease and in patients after liver transplantation. However, it is still unknown in these scenarios how the virus-specific CD4 T cell repertoire and the signals that govern the differentiation and maturation of T cell responses are altered specifically altered. 

Funding

Sonderforschungsbereich-TRR179 (Deutsche Forschungsgemeinschaft, DFG)

Exzellenz-Stipendium 2021 (Else-Kröner-Fresenius-Stiftung, EKFS)

TTU Hepatitis (Deutsches Zentrum für Infektionsforschung, DZIF)

  1. Wild K, Smits M, Killmer S, Strohmeier S, Neumann-Haefelin C, Bengsch B, Krammer F, Schwemmle M, Hofmann M, Thimme R, Zoldan K, Boettler T. 2021
    Pre-existing immunity and vaccine history determine hemagglutinin-specific CD4 T cell and IgG response following seasonal influenza vaccination. Nat Commun. 8;12(1):6720.

  2. Zoldan K, Ehrlich S, Killmer S, Wild K, Smits M, Russ M, Globig AM, Hofmann M, Thimme R, Boettler T. 2021
    Th1-Biased Hepatitis C Virus-Specific Follicular T Helper-Like Cells Effectively Support B Cells After Antiviral Therapy. Front Immunol. 30;12:742061. 

  3. Basho K, Zoldan K, Schultheiss M, Bettinger D, Globig AM, Bengsch B, Neumann-Haefelin C, Klocperk A, Warnatz K, Hofmann M, Thimme R, Boettler T. 2021
    IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis. J Hepatol. 74(3):649-660.

  4. Schulien I, Kemming J, Oberhardt V, Wild K, Seidel LM, Killmer S, Sagar, Daul F, Salvat Lago M, Decker A, Luxenburger H, Binder B, Bettinger D, Sogukpinar O, Rieg S, Panning M, Huzly D, Schwemmle M, Kochs G, Waller CF, Nieters A, Duerschmied D, Emmerich F, Mei HE, Schulz AR, Llewellyn-Lacey S, Price DA, Boettler T*, Bengsch B*, Thimme R*, Hofmann M*, Neumann-Haefelin C*. 2021
    Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells. Nat Med. 27(1):78-85.

  5. Smits M, Zoldan K, Ishaque N, Gu Z, Jechow K, Wieland D, Conrad C, Eils R, Fauvelle C, Baumert TF, Emmerich F, Bengsch B, Neumann-Haefelin C, Hofmann M, Thimme R, Boettler T. 2020
    Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination. J Clin Invest. 130(2):998-1009.

  6. Jacobi FJ, Wild K, Smits M, Zoldan K, Csernalabics B, Flecken T, Lang J, Ehrenmann P, Emmerich F, Hofmann M, Thimme R, Neumann-Haefelin C, Boettler T. 2019
    OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection. J Hepatol. 70(6):1103-1113.

  7. Adam L, Zoldan K, Hofmann M, Schultheiss M, Bettinger D, Neumann-Haefelin C, Thimme R, Boettler T. 2018
    Follicular T Helper Cell Signatures in Primary Biliary Cholangitis and Primary Sclerosing Cholangitis. Hepatol Commun. 7;2(9):1051-1063.

  8. Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. 2016
    Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections. Gastroenterology. 150(3):696-706.e3.

  9. Boettler T, Schneider D, Cheng Y, Kadoya K, Brandon EP, Martinson L, Herrath MV. 2016
    Pancreatic tissue transplanted in TheraCyte™ encapsulation devices are protected and prevent hyperglycemia in a mouse model of immune-mediated diabetes. Cell Transplant. 25(3):609-14.

  10. Boettler T, Choi YS, Salek-Ardakani S, Cheng Y, Moeckel F, Croft M, Crotty S, von Herrath M. 2013
    Exogenous OX40 stimulation during lymphocytic choriomeningitis virus infection impairs follicular Th cell differentiation and diverts CD4 T cells into the effector lineage by upregulating Blimp-1. J Immunol. 15;191(10):5026-35.

  11. Boettler T, Pagni PP, Jaffe R, Cheng Y, Zerhouni P, von Herrath M. 2013
    The clinical and immunological significance of GAD-specific autoantibody and T-cell responses in type 1 diabetes. J Autoimmun. 44:40-8.

  12. Boettler T, Moeckel F, Cheng Y, Heeg M, Salek-Ardakani S, Crotty S, Croft M, von Herrath MG. 2012
    OX40 facilitates control of a persistent virus infection. PLoS Pathog. 8(9):e1002913.

  13. Boettler T, Cheng Y, Ehrhardt K, von Herrath M. 2012
    TGF-β blockade does not improve control of an established persistent viral infection. Viral Immunol. 25(3):232-8.

  14. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R. 2006
    Expression of the interleukin-7 receptor alpha chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol. 80(7):3532-40.

  15. Boettler T, Spangenberg HC, Neumann-Haefelin C, Panther E, Urbani S, Ferrari C, Blum HE, von Weizsäcker F, Thimme R. 2005
    T cells with a CD4+CD25+ regulatory phenotype suppress in vitro proliferation of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol. 79(12):7860-7.

  1. Maier A, Kaeser R, Thimme R, Boettler T. 2019
    Acute pancreatitis and vasoplegic shock associated with leptospirosis - a case report and review of the literature. BMC Infect Dis. 8;19(1):395.

  2. Bettinger D, Martin D, Rieg S, Schultheiss M, Buettner N, Thimme R, Boettler T. 2018
    Treatment with proton pump inhibitors is associated with increased mortality in patients with pyogenic liver abscess. Aliment Pharmacol Ther. 47(6):801-808.

  3. Boettler T, Lutz L, Schmidt N, Thimme R, Neumann-Haefelin C. 2015
    An uncommon presentation of a common pathogen. Gut. 64(9):1411, 1453. 

  1. Boettler T, Lohmann V, Bartenschlager R. 2019
    [Hepatitis C: From Individual Cure to Worldwide Elimination?]. Dtsch Med Wochenschr. 144(8):535-542.
  2. Luxenburger H, Neumann-Haefelin C, Thimme R, Boettler T. 2018
    HCV-Specific T Cell Responses During and After Chronic HCV Infection. Viruses. 17;10(11).
  3. Boettler T, Thimme R. 2018
    Lost in Inflammation: The Functional Conversion of Regulatory T Cells in Acute Hepatitis A Virus Infection. Gastroenterology. 154(4):798-800.
  4. Boettler T, Thimme R, Neumann-Haefelin C. 2015
    [Cure of chronic Hepatitis B and C: vision versus reality]. Dtsch Med Wochenschr. 140(14):1056-62.
  5. Boettler T, Moradpour D, Thimme R, Zoulim F. 2014
    Bridging basic science and clinical research: the EASL Monothematic Conference on Translational Research in Viral Hepatitis. J Hepatol. 61(3):696-705.
  6. Boettler T, von Herrath M. 2012
    IL-7 receptor α blockade, an off-switch for autoreactive T cells. Proc Natl Acad Sci U S A. 31;109(31):12270-1.
  7. Boettler T, Cunha-Neto E, Kalil J, von Herrath M. 2012
    Can an immune-regulatory vaccine prevent HIV infection? Expert Rev Anti Infect Ther. 10(3):299-305.
  8. Boettler T, von Herrath M. 2011
    Protection against or triggering of Type 1 diabetes? Different roles for viral infections. Expert Rev Clin Immunol. 7(1):45-53.

Group of Peter Hasselblatt

PD Dr. Peter Hasselblatt (Group leader) 

+49 (0) 761/270-34010

Dr. Lena Mayer 

 

Birgit Hockenjos (Techn.) 

+49 (0) 761/270-35400

Pius Martin (MD student) 

 

Nadine Reuter (MD student)

 

Felix Röttele (PhD student) 

+49 (0) 761/270-33962

Jonah Szentandrasi (MD student)

 

Frederike Thielen (MD student) 

+49 (0) 761/270-35400

 

Research interest

The concerted action of molecular signaling pathways activated in response to liver damage and inflammation determines the outcome of liver disease. Many lines of evidence suggest that the transcription factor c-Jun, a member of the AP-1 transcription factor, is an essential mediator of many of these hepatic stress responses. We are therefore aiming to dissect its functions in inflammatory liver disease and cancer by studying respective mouse models and patient material. We have previously shown that c-Jun expression indeed promotes hepatocyte survival in a variety of disease models including acute T-cell mediated hepatitis as well as during endoplasmic reticulum stress. Ongoing studies identified c-Jun as important molecular link between liver inflammation and cancer in a mouse model of hepatitis B virus-related tumorigenesis. In addition, we are dissecting the impact of c-Jun on the transition from non-alcoholic fatty liver disease to steatohepatitis in mice and patients.

Another focus of our research is on extracellular ATP signaling in the liver and intestine. ATP release to the extracellular compartment occurs in response to cell death and diverse stress stimuli and is increasingly recognized as important “danger signal” and mediator of subsequent inflammatory responses, which are mediated by binding of ATP to purinergic P2 receptors. We have shown that ATP is indeed released during acute hepatitis in mice. Mice lacking P2Y2R, which is the most abundant P2Y receptor isoform in the liver, are protected from hepatitis. This phenotype is due to synergistic but cell-type specific functions of P2Y2R expression, which mediates chemotaxis of neutrophils to the liver and promotes hepatocyte cell death. These findings suggest that inhibition of P2 receptor function may be a promising therapeutic approach for inflammatory liver disease. We are therefore further dissecting the functions of this receptor family during hepatitis and liver tumorigenesis.

Purinergic P2Y₂ receptors promote neutrophil infiltration and hepatocyte death in mice with acute liver injury. Ayata CK, Ganal SC, Hockenjos B, Willim K, Vieira RP, Grimm M, Robaye B, Boeynaems JM, Di Virgilio F, Pellegatti P, Diefenbach A, Idzko M, Hasselblatt P. (2012) Gastroenterology 143(6):1620-1629.

The transcription factor c-Jun protects against liver damage following activated β-Catenin signaling. Trierweiler C, Blum HE, Hasselblatt P. (2012) PLoS One 7(7):e40638.

The transcription factor c-Jun protects against sustained hepatic endoplasmic reticulum stress thereby promoting hepatocyte survival. Fuest M, Willim K, MacNelly S, Fellner N, Resch GP, Blum HE, Hasselblatt P. (2012) Hepatology. 55(2):408-18.

Impairment of hepatic growth hormone and glucocorticoid receptor signaling causes steatosis and hepatocellular carcinoma in mice. Mueller KM, Kornfeld JW, Friedbichler K, Blaas L, Egger G, Esterbauer H, Hasselblatt P, Schlederer M, Haindl S, Wagner KU, Engblom D, Haemmerle G, Kratky D, Sexl V, Kenner L, Kozlov AV, Terracciano L, Zechner R, Schuetz G, Casanova E, Pospisilik JA, Heim MH, Moriggl R. (2011) Hepatology. 54(4):1398-409.

The role of the transcription factor AP-1 in colitis-associated and beta-catenin-dependent intestinal tumorigenesis in mice. Hasselblatt P, Gresh L, Kudo H, Guinea-Viniegra J, Wagner EF. (2008) Oncogene 27(47):6102-9.

Development of pulmonary fibrosis through a pathway involving the transcription factor Fra-2/AP-1. Eferl R*, Hasselblatt P*, Rath M, Popper H, Zenz R, Komnenovic V, Idarraga MH, Kenner L, Wagner EF. (2008) Proc Natl Acad Sci U S A 105(30):10525-30. (*equal contribution)

Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Hasselblatt P, Rath M, Komnenovic V, Zatloukal K, Wagner EF. (2007) Proc Natl Acad Sci U S A 104(43):17105-10

Group of Maike Hofmann and Robert Thimme

Prof. Dr. Maike Hofmann (Group leader)

+49 (0) 761/270-35091

Prof. Dr. Robert Thimme (Group leader) 

+49 (0) 761/270-34040

Dr. Catrin Tauber (Lab Manager)

+49 (0) 761/270-39110

Özlem Sogukpinar (Dipl. Biol.)(Lab Manager)

+49 (0) 761/270-35090

Melissa Achenbach (Master student)

+49 (0) 761/270-33960

Ceren Atila (TA)

+49 (0) 761/270-35090

Liane Bauersfeld (TA)

+49 (0) 761/270-35090

Mara Baumeister (Hiwi)

+49 (0) 761/270-35090

Fabian Beier (TA)

+49 (0) 761/270-35090

Leonard Bein-Heß (Clinician Scientist)

 

Wasihun Hailemichael Belayneh (PhD student)

+49 (0) 761/270-35110

Aparna Cherukunnath (PhD student)

+49 (0) 761/270-33962

Daniel Eckert (MD student)

 

Anne Gräser (MD student)

 

Philipp Hafkemeyer (MD student)

+49 (0) 761/270-33960

Dr. Margaux Heuschkel (PostDoc)

+49 (0) 761/270-33961

Hannah Jacob (Bachelor student)

+49 (0) 761/270-35090

Vivien Karl (PhD student)

+49 (0) 761/270-33961

Nikhil Kulkarni (PhD student)

+49 (0) 761/270-33962

Anastasia Kremser (Master student)

 

Lysann Mack (Azubi)

+49 (0) 761/270-35090

Noah Pascual Maier (MD student)

+49 (0) 761/270-33960

David Reeg (MD student)

 

Matthias Reinscheid (PhD student)

+49 (0) 761/270-33962

Dr. Charlotte Rennert (Clinician scientist) 

 

Fiona Seger (MD student)

+49 (0) 761/270-33960

Kelly Siebel-Achenbach (Azubi)

+49 (0) 761/270-35090

Eva Stockinger (MD student) 

 

Anja Wahl-Feuerstein (MTA)

+49 (0) 761/270-35400

Dr. Natascha Röhlen (Clinician scientist) 

+49 (0) 761/270-27751

Niklas Vesper (PhD student)

+49 (0) 761/270-33960

Innate and adaptive immunity in viral hepatitis and hepatocellular carcinoma

T cell responses play an important role in the outcome of hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus and hepatitis E virus (HEV) infection, e.g. viral elimination versus persistence. However, multiple mechanisms can lead to the failure of the virus-specific T cell response. These mechanisms include primary T cell failure, T cell exhaustion, the emergence of viral escape mutants, as well as T cell dysfunction. Furthermore, genetic factors such as the individual HLA allele background play an important role in the outcome of infection. Once viral persistence has been established, HBV or HCV infection can progress to liver fibrosis and cirrhosis with an enhanced risk for HCC. Tumor-specific T cells are thought to contribute to cancer control.

The focus of our group is the identification and characterization of virus-specific CD4+ and CD8+ T cell responses during acute and chronic HBV, HCV, HDV and HEV infection and the analysis of adaptive and innate immune responses against cancer. A specific focus is on the identification of the molecular determinants of T cell exhaustion and how this can be reversed in the setting of chronic viral infection and cancer. Indeed, in own previous work we could recently show that antigen-specific CD8+ T cells are heterogenous consisting of memory-like and terminally exhausted cells and that removal of antigen, for example by direct acting antiviral therapy leads to a disappearance of highly exhausted, but maintenance of a memory-like CD8+ T cell population. This memory-like population is characterized by specific phenotypical functional metabolic and transcriptional characteristics. On the CD4+ T cell level, we are interested in the lineage commitment of virus-specific CD4 helper T cells in different phases of viral hepatitis. Overall, these translational studies should give novel targets for immune therapy and help to identify biomarkers for prediction of response of different antiviral or immunotherapeutic therapies, such as checkpoint blockade. Another focus in our group is the analysis of innate immune responses in viral hepatitis and cancer with a specific focus on NK cells and gamma delta T cells. For example, we could recently show the expansion of adaptive/memory-like NK cells in chronic HBV virus infection. A further detailed understanding of the biological role of these innate subsets and their interaction with adaptive immune responses will be essential for the development of novel immunotherapeutic approaches.

We currently co-operate with the groups of

  • Prof. Dr. D. Zehn, München (School of Life Sciences Weihenstephan)
  • Prof. Dr. H. Pircher, Freiburg (Institute of Immunology)
  • Dr. Paul Klenerman, Oxford (Nuffield Department of Medicine)
  • Dr. Volker Lohmann and Prof. Dr. Ralf Bartenschlager, Heidelberg (Institute of Molecular Virology)
  • Prof. Dr. Thomas Baumert, Strassbourg (INSERM Strassbourg)
  • Dr. David Price, Cardiff (School of Medicine)
  • Dr. Dominic Grün, Freiburg (Max-Planck-Institute of Immunobiology and Epigenetics)
  • Prof. Dr. Jörg Timm, Düsseldorf (Institute for Virology)
  • E. John Wherry, PhD, University of Pennsylvania (Penn Institute for Immunology)
  • Naveed Ishaque, Heidelberg (Heidelberg Center for Personalized Oncology at the German Research Center) and Christian Conrad, Heidelberg (Alfred-Weber-Institute for Economics)
  • Manching Ku, Freiburg (Clinic for Pediatric Hematology & Oncology) and Melanie Börries, Freiburg (Institute for Molecular Medicine)

Our studies are currently sponsored by:

  • Sonderforschungsbereich-TRR179 (Deutsche Forschungsgemeinschaft, DFG)
  • Sonderforschungsbereich 1160: IMPATH (Deutsche Forschungsgemeinschaft, DFG)
  • Else Kröner-Fresenius-Stiftung: MOTI-VATE
  • Europäische Union: Horizon 2020: HEP-CAR
  • Deutsches Zentrum für Infektionsforschung DZIF (BMBF)

  1. Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpinar Ö, Ni Y, Urban S, Zimmermann P, Nassal M, Emmerich F, Price DA, Bengsch B, Luxenburger H, Neumann-Haefelin C, Hofmann M, Thimme R. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 2019 May;68(5):905-915
  2. Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M, Thimme R. TCF1(+) hepatitis C virus-specific CD8(+) T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017; May 3;8:15050
  3. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, Pradervand S, Thimme R, Zehn D, Held W. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity. 2016; 45(2):415-27
  4. Hoh A, Heeg M, Ni Y, Schuch A, Binder B, Hennecke N, Blum HE, Nassal M, Protzer U, Hofmann M, Urban S, Thimme R. Hepatitis B Virus-Infected HepG2hNTCP Cells Serve as a Novel Immunological Tool To Analyze the Antiviral Efficacy of CD8+ T Cells In Vitro. J Virol. 2015; 89(14):7433-8
  5. Martin B, Hennecke N, Lohmann V, Kayser A, Neumann-Haefelin C, Kukolj G, Böcher WO, Thimme R. Restoration of HCV-specific CD8+ T cell function by interferon-free therapy. J Hepatol. 2014; 61(3):538-43
  6. Seigel B, Bengsch B, Lohmann V, Blum HE, Thimme R. Factors that determine the antiviral efficacy of HCV-specific CD8+ T cells, ex vivo. Gastroenterology 2013, 144:426-36
  7. Schmidt J, Iversen A, Tenzer, Gosticke, Priced, Lohmann V, Distler U, Bowness P, Schild, Blum HE, Klenerman P, Neumann-Haefelin C., Thimme R. Rapid antigen processing and presentation of a protective and immunodominant HLA-B*27-restricted Hepatitis C virus-specific CD8+ T-cell epitope. PLoS Pathog 2012, 8:e1003042
  8. Bengsch B, Seigel B, Flecken T, Wolanski J, Blum HE, Thimme R. Human Th17 cells express high levels of enzymatically active Dipeptidylpeptidase IV (CD26). J Immunol 2012, 188:5438-47
  9. Billerbeck E, Kang YH, Walker L, Lockstone H, Grafmueller S, Fleming V, Flint J, Willberg CB, Bengsch B, Seigel B, Ramamurthy N, Zitzmann N, Barnes EJ, Thevanayagam J, Bhagwanani A, Leslie A, Oo YH, Kollnberger S, Bowness P, Drognitz O, Adams DH, Blum HE, Thimme R*, Klenerman P*. (equal contribution) Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A. 2010, 107:3006-11
  10. Neumann-Haefelin C, Timm J, Schmidt J, Kersting N, Fitzmaurice K, Oniangue-Ndza C, Kemper MN, Humphreys I, McKiernan S, Kelleher D, Lohmann V, Bowness P, Huzly D, Rosen HR, Kim AY, Lauer GM, Allen TM, Barnes E, Roggendorf M, Blum HE, Thimme R. Protective effect of human leukocyte antigen B27 in hepatitis C virus infection requires the presence of a genotype-specific immunodominant CD8+ T-cell epitope. Hepatology 2010, 51:54-62
  11. Jo J, Aichele U, Kersting N, Klein R, Aichele P, Bisse E, Sewell AK, Blum HE, Bartenschlager R, Lohmann V, Thimme R. Analysis of CD8+ T cell-mediated inhibition of hepatitis C virus replication using a novel immunological model. Gastroenterology 2009, 136:1391-401
  12. Neumann-Haefelin C, Timm J, Spangenberg HC, Wischnowski N, Nazarova N, Kersting N, Roggendorf M, Allen TM, Blum HE, Thimme R. Virological and immunological determinants of intrahepatic virus-specific CD8+ T cell failure in chronic hepatitis C virus infection. Hepatology 2008, 47:1824-36
  13. Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R. Expression of the interleukin 7 receptor alpha chain on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells in acute resolving hepatitis B virus infection. J Virol 2006, 80:3532-40

Group of Christoph Neumann-Haefelin

Prof. Dr. Christoph Neumann-Haefelin ( Group leader) 

+49 (0) 761/270-32800

Anna-Lena Denecke (PhD student)

+49 (0) 761/270-35110

Dr. Julia Lang-Meli (Clinician Scientist)

 

Dr. Hendrik Luxenburger (Clinician Scientist)

 

Michelle Maas (PhD student)

+49 (0) 761/270-35110

In addition, we work in close cooperation with the other groups of the Translational EXperimental IMmunology lab (TEXIMMED2-FR)

Research interest

The focus of our research group are protective immune responses as well as immunopathology in the context of viral hepatitis (hepatitis B, C, D and E), hepatocellular carcinoma (HCC), and SARS-CoV-2 infection (COVID-19). A specific interest are mechanisms that lead to the failure of protective immune responses, including CD8+ T-cell failure and viral escape mutations. Long-term translational goals of our research are the development of novel antiviral strategies contributing to functional cure of hepatitis B and D virus infection, successful vaccination strategies against hepatitis C virus, and novel treatment options for immunocompromised patients suffering from chronic hepatitis E virus infection. In HCC, improved immunotherapies with reduced risk of adverse effects such as checkpoint inhibitor associated autoimmune disorders are an important goal. Finally, we want to contribute to an enhanced understanding of protective immunity following SARS-CoV-2 infection and vaccination, allowing an informed strategy against this ongoing pandemics.

Funding

Our studies are supported by:

  • Sonderforschungsbereich-TRR179 (Deutsche Forschungsgemeinschaft, DFG)
  • Sonderforschungsbereich 1160: IMPATH (Deutsche Forschungsgemeinschaft, DFG)
  • NAKSYS (Else Kröner-Fresenius-Stiftung)
  • DZIF TTU Hepatitis (BMBF)
  • Sonderfördermaßnahme COVID-19 (MWK Baden-Württemberg)

  1. Schulien I*, Kemming J*, Oberhardt V*, Wild K*, Seidel LM*, Killmer S, Sagar, Daul F, Salvat Lago M, Decker A, Luxenburger H, Binder B, Bettinger D, Sogukpinar O, Rieg S, Panning M, Huzly D, Schwemmle M, Kochs G, Waller CF, Nieters A, Duerschmied D, Emmerich F, Mei HE, Schulz AR, Llewellyn-Lacey S, Price DA, Boettler T*, Bengsch B*, Thimme R*, Hofmann M*, Neumann-Haefelin C*. Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells. Nat Med 2021;27(1):78-85
  2. Schwabenland M, Salié H, Tanevski J, Killmer S, Lago MS, Schlaak AE, Mayer L, Matschke J, Püschel K, Fitzek A, Ondruschka B, Mei HE, Boettler T, Neumann-Haefelin C, Hofmann M, Breithaupt A, Genc N, Stadelmann C, Saez-Rodriguez J, Bronsert P, Knobeloch KP, Blank T, Thimme R, Glatzel M, Prinz M, Bengsch B. Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions. Immunity 2021 (in press, online available)
  3. Urban S*, Neumann-Haefelin C*, Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut 2021 (in press, online available)
  4. Bettinger D, Sturm L, Pfaff L, Hahn F, Kloeckner R, Volkwein L, Praktiknjo M, Lv Y, Han G, Huber JP, Boettler T, Reincke M, Klinger C, Caca K, Heinzow H, Seifert LL, Weiss KH, Rupp C, Piecha F, Kluwe J, Zipprich A, Luxenburger H, Neumann-Haefelin C, Schmidt A, Jansen C, Meyer C, Uschner FE, Brol MJ, Trebicka J, Rössle M, Thimme R, Schultheiss M. Refining prediction of survival after TIPS with the novel Freiburg index of post-TIPS survival. J Hepatol 2021;74(6):1362-1372
  5. Hensel N, Gu Z, Sagar, Wieland D, Jechow K, Kemming J, Llewellyn-Lacey S, Gostick E, Sogukpinar O, Emmerich F, Price DA, Bengsch B, Boettler T, Neumann-Haefelin C, Eils R, Conrad C, Bartenschlager R, Grün D, Ishaque N, Thimme R, Hofmann M. Memory-like HCV-specific CD8<sup>+</sup> T cells retain a molecular scar after cure of chronic HCV infection. Nat Immunol 2021;22(2):229-239.
  6. Basho K, Zoldan K, Schultheiss M, Bettinger D, Globig AM, Bengsch B, Neumann-Haefelin C, Klocperk A, Warnatz K, Hofmann M, Thimme R, Boettler T. IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis. J Hepatol 2021;74(3):649-660
  7. Heim K, Binder B, Sagar, Wieland D, Hensel N, Llewellyn-Lacey S, Gostick E, Price DA, Emmerich F, Vingerhoet H, Kraft ARM, Cornberg M, Boettler T, Neumann-Haefelin C, Zehn D, Bengsch B, Hofmann M, Thimme R. TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut 2020 (in press, online available)
  8. Smits M, Zoldan K, Ishaque N, Gu Z, Jechow K, Wieland D, Conrad C, Eils R, Fauvelle C, Baumert TF, Emmerich F, Bengsch B, Neumann-Haefelin C, Hofmann M, Thimme R, Boettler T. Follicular T helper cells shape the HCV-specific CD4+ T cell repertoire after virus elimination. J Clin Invest 2020;130(2):998-1009
  9. Tauber C, Schultheiss M, Luca R, Buettner N, Llewellyn-Lacey S, Emmerich F, Zehe S, Price DA, Neumann-Haefelin C, Schmitt-Graeff A, Hofmann M, Thimme R. Inefficient induction of circulating TAA-specific CD8+ T-cell responses in hepatocellular carcinoma. Oncotarget 2019;10(50):5194-5206
  10. Jacobi FJ*, Wild K*, Smits M, Zoldan K, Csernalabics B, Flecken T, Lang J, Ehrenmann P, Emmerich F, Hofmann M, Thimme R, Neumann-Haefelin C, Boettler T. OX40 stimulation and PD-L1 blockade synergistically augment HBV-specific CD4 T cells in patients with HBeAg-negative infection. J Hepatol 2019 Jun;70(6):1103-1113
  11. Kemming J*, Reeves E*, Nitschke K, Widmeier V, Emmerich F, Hermle T, Gostick E, Walker A, Timm J, Price DA, Hofmann M, Thimme R, James E*, Neumann-Haefelin C*. ERAP1 allotypes shape the epitope repertoire of virus-specific CD8+ T cell responses in acute hepatitis C virus infection. J Hepatol 2019;70(6):1072-1081
  12. Karimzadeh H*, Kiraithe MM*, Oberhardt V*, Salimi Alizei E, Bockmann J, Schulze Zur Wiesch J, Budeus B, Hoffmann D, Wedemeyer H, Cornberg M, Krawczyk A, Rashidi-Alavijeh J, Rodríguez-Frías F, Casillas R, Buti M, Smedile A, Alavian SM, Heinold A, Emmerich F, Panning M, Gostick E, Price DA, Timm J, Hofmann M, Raziorrouh B, Thimme R, Protzer U, Roggendorf M*, Neumann-Haefelin C*. Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8<sup>+</sup> T Cells and Evolve at the Population Level. Gastroenterology 2019;156(6):1820-1833.
  13. Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpinar Ö, Ni Y, Urban S, Zimmermann P, Nassal M, Emmerich F, Price DA, Bengsch B, Luxenburger H, Neumann-Haefelin C, Hofmann M, Thimme R. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut 2019;68(5):905-915
  14. Schuch A, Zecher BF, Müller PA, Correia MP, Daul F, Rennert C, Tauber C, Schlitt K, Boettler T, Neumann-Haefelin C, Hengel H, Pircher H, Cerwenka A, Thimme R, Hofmann M. NK-cell responses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection. J Hepatol. 2019 Mar;70(3):351-360

Prof. Dr. Maike Hofmann

Head of the Translational Experimental Immunology Section
Head of Research MED II

+49 (0) 761 270-35091

maike.hofmann@uniklinik-freiburg.de