Project Description

TP01A: Metabolic regulation of T cell exhaustion in chronic HBV infection.

HBV-specific CD8 T cells persist in chronic HBV infection and are characterized by an altered cytokine function profile with reduced effector functions compared to acute resolving HBV infection. In addition, they express a set of inhibitory receptors, in agreement with phenotoypes of exhausted T cells (TEX).
However, there is a heterogeneity in features of exhaustion in HBV-specific T cells. Our own results as well as others suggest the existence of developmental hierarchies within the pool of TEX that can be characterized by a changing set of inhibitory receptor expression, transcriptional regulation and altered cellular metabolism. These different TEX subsets are also linked with different functional profiles that can correlate with disease stage and are influenced by antiviral therapy.
Within the scope of my association with the TRR179, I plan to investigate important aspects of the metabolic regulation of T cell exhaustion in chronic hepatitis B.
Specifically, our research will involve (1) the characterization of the T-cell metabolism profile in chronic HBV infection, (2) the functional metabolic characterization of TEX as well as the manipulation of TEX in chronic HBV infection and (3) the effects of HBV therapy on TEX metabolism.
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
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)
Bengsch, B., and Chang, K.M. (2016). Evolution in Our Understanding of Hepatitis B Virus Virology and Immunology. Clin Liver Dis 20, 629-644.
Bengsch, B., Johnson, A.L., Kurachi, M., Odorizzi, P.M., Pauken, K.E., Attanasio, J., Stelekati, E., McLane, L.M., Paley, M.A., Delgoffe, G.M., and Wherry, E.J. (2016). Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45, 358-373.
Bengsch, B., Martin, B., and 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, 1212-1219.