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Group of Tobias Böttler

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. 

Members

Prof. Dr. Tobias Böttler (Group leader)   0761/270-34043
   
Benedikt Csernalabics (MD Student) 0761/270-35100
Jana Gawron (Master student) 0761/270-35100
Dr. Rafael Käser (Clinician scientist) 0761/270-35500
Lara Kelsch (PhD student) 0761/270-35100
Stefan Marinescu (MD Student) 0761/270-35100
Jill Werner (PhD student) 0761/270-35100
Katharina Wild (PhD student) 0761/270-35100

 

 

   

Funding

Sonderforschungsbereich-TRR179 (Deutsche Forschungsgemeinschaft, DFG)

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

TTU Hepatitis (Deutsches Zentrum für Infektionsforschung, DZIF)

Selected Publications (original research)

  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.

Selected Publications (clinical research and case reports)

  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. 

Selected Publications (review articles, editorials)

  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.