Project Description

TP04: Characterization of follicular T helper cell responses in viral hepatitis

CD4+ T follicular helper (Tfh) cells are specialized in providing help to B cells and facilitating potent antibody responses as well as their signature cytokine IL-21 that supports CD8+ T cell responses. We propose to characterise key determinants of a successful Tfh response in acute resolving Hepatitis B virus (HBV) infection, in HBV vaccinees and by employing a mouse model of acute HBV infection. The long-term goal of this application is to design therapeutic approaches involving Tfh cells for the treatment of chronic HBV infection through induction of anti-HBs-antibodies and to support HBV-specific CD8+ T cells through Tfh cell-derived IL-21.
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. 2019. Follicular T helper cells shape the HCV-specific CD4 T cell repertoire after viral elimination. J Clin Invest. 130(2):998-1009
Ackermann C, Smits M, Woost R, Eberhard JM, Peine S, Kummer S, Marget M, Kuntzen T, Kwok WW, Lohse AW, Jacobs T, Boettler T, Schulze Zur Wiesch J. 2019. HCV-specific CD4+ T cells of patients with acute and chronic HCV infection display high expression of TIGIT and other co-inhibitory molecules. Sci Rep. 9(1):10624. doi: 10.1038/s41598-019-47024-8.
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. doi: 10.1016/j.jhep.2019.02.016
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. doi: 10.1053/j.gastro.2018.02.003.
Luxenburger H, Neumann-Haefelin C, Thimme R, Boettler T. 2018. HCV-Specific T Cell Responses During and After Chronic HCV Infection. Viruses. 10(11). pii: E645. doi: 10.3390/v10110645. Review.
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. 2018. NK-cell responses are biased towards CD16-mediated effector functions in chronic hepatitis B virus infection. J Hepatol. 70(3):351-360. doi: 10.1016/j.jhep.2018.10.006.
Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boettler T. 2015. Follicular T helper cell signatures on virus-specific CD4 T cells during acute and chronic HCV-infection. Gastroenterology 150(3):696-706.
Boettler T, Choi YS, Salek-Ardakani S, Cheng Y, Moeckel F, Croft M, Crotty S, von Herrath M. 2013b. 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 191:5026-35.
Boettler T, Pagni PP, Jaffe R, Cheng Y, Zerhouni P, von Herrath M. 2013a. The clinical and immunologi- cal significance of GAD-specific autoantibody and T-cell responses in type 1 diabetes. J Autoimmun 44:40-8.
Boettler T, Moeckel F, Cheng Y, Heeg M, Salek-Ardakani S, Crotty S, Croft M, von Herrath MG. 2012b. OX40 facilitates control of a persistent virus infection. PLoS Pathog 8:e1002913.
Boettler T, Cheng Y, Ehrhardt K, von Herrath M. 2012a. TGF-β blockade does not improve control of an established persistent viral infection. Viral Immunol 25:232-8.
Thimme R, Neagu M, Boettler T, Neumann-Haefelin C, Kersting N, Geissler M, Makowiec F, Obermaier R, Hopt UT, Blum HE, Spangenberg HC. 2008. Comprehensive analysis of the alpha-fetoprotein-specific CD8+ T cell responses in patients with hepatocellular carcinoma. Hepatology 48:1821-33.
Boettler T, Panther E, Bengsch B, Nazarova N, Spangenberg HC, Blum HE, Thimme R. 2006. Expres- sion 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 80:3532-40.
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 prolif- eration of virus-specific CD8+ T cells during chronic hepatitis C virus infection. J Virol 79:7860-7.