Project Description

TP20: Impact of interferon-stimulated genes on virus-specific CD8+ T cells and NK cells in viral hepatitis

The overall aim of this project is to identify the role of Interferon-stimulated genes (ISGs) in T-cell and NK-cell differentiation and function in order to determine the impact on the failure of the cytotoxic immune response in chronic viral hepatitis. For this, we will determine ISG signatures and the responsiveness towards interferons of different virus-specific CD8+ T-cell and NK-cell subsets in viral hepatitis by RNAseq, ATACseq and high-dimensional FACS analyses complemented by in vitro assays following gain- and loss-of-function experiments.
A. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, Hösslin M, Cullen J, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen C, Thimme R*, Youngblood B*, Zehn D*. 2019. Tox reinforces the phenotype and longevity of dysfunctional T cell populations during chronic viral infection. Nature. 571(7764):265-269 * co-corresponding authors
B. Karimzadeh H*, Kiraithe MM*, Oberhardt V*, Salimi Alizei E, Bockmann J, Schulze Zur Wiesch J, Bude-us 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 Popula-tion Level. Gastroenterology. 156(6):1820-1833 *equal contribution
C. 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
D. Schuch A, Salimi Alizei E*, Heim K*, Wieland D, Kiraithe MM, Kemming J, Llewellyn-Lacey S, Sogukpi-nar 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 HBVcore- versus HBVpolymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. GUT. 68(5) *equal senior authorship
E. Schuch A*, Zecher BF*, Müller PA, Correia MP, Daul F, Rennert C, Tauber C, Schlitt K, Böttler T, Neumann-Haefelin C, Hengel H, Pircher H, Cerwenka A, Thimme R, Hofmann M. 2019. NK-cell respons-es are based towards CD16-mediated effector functions in chronic hepatitis B virus infection. J He-patol. 70(3):351-360 *equal contribution
F. 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. 23;9:756 *equal contribution
G. 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, Razior-rouh 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). pii: e01891-17
H. 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 Ex-pression of FOXO1. Cell Rep. 22(13):3454-3467
I. Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hof-mann M*, Thimme R*. 2017. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessa-tion of chronic antigen stimulation. Nat Commun. 8:15050 *equal senior authorship
J. 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. 2016. T Cell Factor 1-Expressing Memory-like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Im-munity. 45(2):415-2