Project Description

TP21: Metabolic regulation of the virus-specific T cell response in viral hepatitis

Exhausted virus-specific T cells with reduced antiviral function are enriched during unsuccessful immune responses in patients with chronic Hepatitis B and C infection. Our previous work suggest that this is due to regulation of cellular metabolism. In this project, we aim to understand by a combination of cytometry and metabolic analyses how changes in T cell metabolism influence the T cell response in viral hepatitis. We hypothesize that different metabolic programming secondary to differences in antigen recognition and inflammation determine the severity of T cell exhaustion.
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. Characterization of pre-existing and induced SARS-CoV-2-specific CD8+ T cells. Nat Med. 2020 Nov 12. doi: 10.1038/s41591-020-01143-2. (TP01, TP02, TP11, TP20, TP21)

A. 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, Neu-mann-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 vi-ral load. Gut. 68(5):905-915.
B. Qiu J, Villa M, Sanin DE, Buck MD, O'Sullivan D, Ching R, Matsushita M, Grzes KM, Winkler F, Chang CH, Curtis JD, Kyle RL, Van Teijlingen Bakker N, Corrado M, Haessler F, Alfei F, Edwards-Hicks J, Maggi LB Jr, Zehn D, Egawa T, Bengsch B, Klein Geltink RI, Jenuwein T, Pearce EJ, Pearce EL. 2019. Acetate Promotes T Cell Effector Function during Glucose Restriction. Cell Rep. 27(7):2063-2074.e5
C. 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
D. Bengsch B, Ohtani T, Khan O, Setty M, Manne S, O'Brien S, Gherardini PF, Herati RS, Huang AC, Chang KM, Newell EW, Bovenschen N, Pe'er D, Albelda SM, Wherry EJ. 2018. Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. Immunity. 48(5):1029-1045.e5.
E. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM, Wherry EJ. 2016. Bioenergetic insufficiencies due to metabolic alterations are an early driver of CD8 T cell exhaustion. Immunity. 45(2):358-73.
F. Bengsch B*, Martin B*, Thimme R. 2014. Restoration of HBV-specific CD8+ T-cell function by PD-1 blockade in inactive carrier patients is linked to T-cell differentiation. J Hepatol. 61(6):1212-9
G. 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(2):426-36.
H. Bengsch B*, Jo J*, Seigel B*, Rau SJ*, Schmidt J, Bisse E, Aichele P, Aichele U, Joeckel L, Royer C, Ferreira KS, Borner C, Baumert TF, Blum HE, Lohmann V, Fischer R, Thimme R. 2012. Low perforin ex-pression of early differentiated HCV-specific CD8+ T cells limits their hepatotoxic potential. J Hepatol 57(1):9-16
I. 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 recogni-tion and T cell differentiation. PLoS Pathog 6:e1000947.
J. 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 function-ally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J Virol 80(7):3532-40