Project Description

TP03: Generation of effective antiviral CD4 T cell immunity in viral hepatitis and its association to unique signatures of transcription factors

Recent studies provide evidence for an important role of master transcription factors such as T-bet (T-box expressed in T-cells, Tbx21) to induce effective CD8+ T cell responses. Based on own data and data from others we hypothesize that the detailed characterization of T helper cell lineage-defining master transcription factors will be critical to identify protective signatures of antiviral immune responses. In this project we will therefore primarily define molecular biomarkers associated with success and failure of CD4+ T cell responses as a critical pre-requisite to devise T cell-based immune reconstitution therapies especially in HBV infection.
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. Amino acid substitutions within HLA-B*27-restricted T cell epitopes prevent recognition by hepatitis delta virus-specific CD8+ T cells. J Virol. 2018 Apr 18. pii: JVI.01891-17. doi: 10.1128/JVI.01891-17. (Epub ahead of print)
Raziorrouh B, Sacher K, Tawar RG, Emmerich F, Neumann-Haefelin C, Baumert TF, Thimme R, Boett- ler T. 2016. Follicular T helper cell signatures on virus-specific CD4 T cells during acute and chronic HCV-infection. Gastroenterology 150(3):696-706.e3. doi: 10.1053/j.gastro.2015.11.005
Kurktschiev PD, Raziorrouh B, Schraut W, Backmund M, Wächtler M, Wendtner CM, Bengsch B, Thim- me R, Denk G, Zachoval R, Dick A, Spannagl M, Haas J, Diepolder HM, Jung MC, Gruener NH. 2014. Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet in- duction. J Exp Med 211:2047-59.
Raziorrouh B, Heeg M, Kurktschiev P, Schraut W, Zachoval R, Wendtner C, Wächtler M, Spannagl M, Denk G, Ulsenheimer A, Bengsch B, Pircher H, Diepolder HM, Grüner NH, Jung MC. 2014. Inhibitory Phenotype of HBV-Specific CD4+ T-Cells Is Characterized by High PD-1 Expression but Absent Coregu- lation of Multiple Inhibitory Molecules. PLoS One 9 :e105703.
Raziorrouh B, Ulsenheimer A, Schraut W, Heeg M, Kurktschiev P, Zachoval R, Jung MC, Thimme R, Neumann-Haefelin C, Horster S, Wächtler M, Spannagl M, Haas J, Diepolder HM, Gruener NH. 2011. In- hibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T-cells in patients with chronic infection. Gastroenterology 141: 1422-1431.
Raziorrouh B, Schraut W, Gerlach T, Nowack D, Gruener NH, Ulsenheimer A, Zachoval R, Wächtler M, Spannagl M, Haas J, Diepolder HM, Jung MC. 2010. The immunoregulatory role of CD244 in chronic hepatitis B infection and its inhibitory potential on virus-specific CD8+ T-cell function. Hepatology 52: 1934-1947
Raziorrouh B, Jung MC, Schirren CA, Loehe F, Thiel M, Nitschko H, Diepolder H, Ulsenheimer A, Heeg M, Zachoval R, Gruener NH. 2008. Antiviral therapy for recurrent hepatitis C after liver transplantation: sustained virologic response is related to genotype 2/3 and response at week 12. Eur J Gastroenterol Hepatol 20: 778-783.