Project Description

TP01: Mechanisms of antiviral therapy-induced virus-specific CD8+ T cell restoration in chronic viral hepatitis

In chronic HBV and HCV infection, prolonged antigen recognition by virus-specific CD8+ T cells is accompanied by their dysfunction due to exhaustion. Recent data suggest that CD8+ T-cell exhaustion is at least partially restored after antigen withdrawal. This research programme aims to dissect direct and indirect effects of continuous antigen recognition on the phenotype, molecular signature and antiviral efficacy of HBV- and HCV-specific CD8+ T cells and to investigate their recovery after therapy-induced antigen elimination.
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
Lang J, Neumann-Haefelin C, Thimme R. Immunological cure of HBV infection. 2019. Hepatol Int. 13(2):113-124.
Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hösslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R*, Youngblood B*, Zehn D*. 2019. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 571(7764):265-269. doi: 10.1038/s41586-019-1326-9.
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. 2019 Feb 28. pii: S0168-8278(19)30131-X. doi: 10.1016/j.jhep.2019.02.016. (Epub ahead of print)
Karimzadeh H, Kiraithe MM, Oberhardt V, Alizei ES, Bockmann J, Zur Wiesch JS, 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. 2019. Mutations in Hepatitis D Virus Allow it to Escape Detection by CD8+ T Cells and Evolve at the Population Level. Gastroenterology. 2019 Feb 12. pii: S0016-5085(19)30366-X. doi: 10.1053/j.gastro.2019.02.003. (Epub ahead of print)
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. 2019. 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 Jan 8. pii: gutjnl-2018-316641. doi: 10.1136/gutjnl-2018-316641. (Epub ahead of print)
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.
Pollmann J, Götz JJ, Rupp D, Strauss O, Granzin M, Grünvogel O, Mutz P, Kramer C, Lasitschka F, Lohmann V, Björkström NK, Thimme R, Bartenschlager R, Cerwenka A. 2018. Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis. J Hepatol. 68(3):421-430.
Rehermann B and Thimme R. 2018. Insights from antiviral therapy into immune responses to HBV and HCV infection. Gastroenterology. 156(2):369-383. doi: 10.1053/j.gastro.2018.08.061.
Neumann-Haefelin C and Thimme R. 2018. Entering the spotlight: hepatitis B surface antigen-specific B cells. J Clin Invest. 128(10):4257-4259.
Manske K, Kallin N, König V, Schneider A, Kurz S, Bosch M, Welz M, Cheng RL, Bengsch B, Steiger K, Protzer U, Thimme R, Knolle PA, Wohlleber D. 2018. Outcome of anti-viral immunity in the liver is shaped by the level of antigen expressed in infected hepatocytes. Hepatology. 68(6):2089-2105. doi: 10.1002/hep.30080.
Hofmann M, Wieland D, Pircher H, Thimme R. 2018. Memory vs memory-like: The different facets of CD8+ T-cell memory in HCV infection.Immunol Rev. 283(1):232-237. doi: 10.1111/imr.12642.
Provine NM, Binder B, FitzPatrick MEB, Schuch A, Garner LC, Williamson KD, van Wilgenburg B, Thimme R, Klenerman P, Hofmann M. 2018. Unique and Common Features of Innate-Like Human Vδ2+ γδT Cells and Mucosal-Associated Invariant T Cells. Front Immunol. 9:756. doi: 10.3389/fimmu.2018.00756. eCollection 2018.
Karimzadeh H, Kiraithe MM, Kosinska AD, Glaser M, Fiedler M, Oberhardt V, Salimi Alizei E, Hofmann M, Mok JY, Nguyen M, van Esch WJE, Budeus B, Grabowski J, Homs M, Olivero A, Keyvani H, Rodríguez-Frías F, Tabernero D, Buti M, Heinold A, Alavian SM, Bauer T, Schulze Zur Wiesch J, Raziorrouh B, Hoffmann D, Smedile A, Rizzetto M, Wedemeyer H, Timm J, Antes I, Neumann-Haefelin C, Protzer U, Roggendorf M. 2018. Amino acid substitutions within HLA-B*27-restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. J Virol. 92(13)
Utzschneider DT, Delpoux A, Wieland D, Huang X, Lai CY, Hofmann M, Thimme R, Hedrick SM. 2018. Active Maintenance of T Cell Memory in Acute and Chronic Viral Infection Depends on Continuous Expression of FOXO1. Cell Rep. 22(13):3454-3467.
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.
Grünvogel O, Colasanti O, Lee JY, Klöss V, Belouzard S, Reustle A, Esser-Nobis K, Hesebeck-Brinckmann J, Mutz P, Hoffmann K, Mehrabi A, Koschny R, Vondran FWR, Gotthardt D, Schnitzler P, Neumann-Haefelin C, Thimme R, Binder M, Bartenschlager R, Dubuisson J, Dalpke AH, Lohmann V. Secretion of Hepatitis C Virus Replication Intermediates Reduces Activation of Toll-Like Receptor 3 in Hepatocytes. Gastroenterology. 154(8):2237-2251.e16. doi: 10.1053/j.gastro.2018.03.020.
Pollmann J, Rölle A, Hofmann M, Cerwenka A. 2017. Hepatitis C Virus and Human Cytomegalovirus-Natural Killer Cell Subsets in Persistent Viral Infections. Front Immunol. 8:566. Review
Wieland D, Hofmann M, Thimme R. Overcoming CD8+ T-Cell Exhaustion in Viral Hepatitis: Lessons from the Mouse Model and Clinical Perspectives. 2017. Dig Dis. 35(4):334-338. doi: 10.1159/000456584
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. 2017. Nat Commun. 8:15050. doi: 10.1038/ncomms15050.
Hofmann M, Thimme R. 2016. MAIT be different-persisting dysfunction after DAA-mediated clearance of chronic hepatitis C virus infection. Eur J Immunol. 46(9):2099-102. doi: 10.1002/eji.201646581.
Hoh A, Heeg M, Ni Y, Schuch A, Binder B, Hennecke N, Blum HE, Nassal M, Protzer U, Hofmann M, Urban S, Thimme R. 2015. HBV-infected HepG2hNTCPcells serve as a novel immunological tool to ana- lyse the antiviral efficacy of CD8+ T cells in vitro. J Virol 89:7433-8
Nitschke K, Flecken T, Schmidt J, Gostick E, Marget M, Neumann-Haefelin C, Blum HE, Price DA, Thimme R. 2015. Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus- specific CD8+ T cells in chronic infection. J Virol 89:25-34
Bengsch B, Martin B, Thimme R. 2014. Restoration of HBV-specific CD8+ T cell function by PD-1 block- ade in inactive carrier patients is linked to T cell differentiation. J Hepatol 61:1212-9
Martin B, Hennecke N, Lohmann V, Kayser A, Neumann-Haefelin C, Kukolj G, Böcher WO, Thimme R. 2014. Restoration of HCV-specific CD8+ T cell functions by IFN-free therapy. J Hepatol 61:538-43
Seigel B, Bengsch B, Lohmann V, Bartenschlager R, Blum HE, Thimme R. 2013. Factors that determine the antiviral efficacy of HCV-specific CD8(+) T cells ex vivo. Gastroenterology 144:426-36.
Hofmann M, Oschowitzer A, Kurzhals SR, Krüger CC, Pircher H. 2013. Thymus-resident memory CD8+ T cells mediate local immunity. Eur J Immunol 43:2295-304
Hofmann M, Schweier O, Pircher H. 2012. Different inhibitory capacities of human and mouse KLRG1 are linked to distinct disulfide-mediated oligomerizations. Eur J Immunol 42:2484-90
Hofmann M, Pircher H. 2011. E-cadherin promotes accumulation of a unique memory CD8 T-cell popula- tion in murine salivary glands. Proc Natl Acad Sci USA 108:16741-6
Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, Pircher H, Thimme R. 2010. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog 6:e1000947
Jo J, Aichele U, Kersting N, Klein R, Aichele P, Bisse E, Sewell AK, Blum HE, Bartenschlager R, Loh- mann V, Thimme R. 2009. Analysis of CD8+ T-cell-mediated inhibition of hepatitis C virus replication us- ing a noval immunological model. Gastroenterology 136:1391-401