Analysis of the link between T cell exhaustion and T cell differentiation in human chronic viral infection

• Applicant: Professor Bertram Bengsch, Ph.D.
• Subject Area: Gastroenterology ; Immunology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 253949616

Virus-specific CD8+ T cells play an important role in the control of several highly relevant viral infections, such as Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection. However, in chronic infection, the failure to control the virus is linked to a dysfunction of "exhausted" virus-specific CD8+ T cells to produce antiviral cytokines and to proliferate sufficiently. Exhausted virus-specific CD8* T cells can be functionally invigorated by the blockade of inhibitory receptor pathways, e.g. by PD-1/PD-L1 blockade and are thus a promising target for immunomodulatory therapies. However, although important insights into exhausted virus-specific CD8+ T cells have been obtained, the determinants of T cell exhaustion are currently unclear. In particular, the link between T cell differentiation and T cell exhaustion, the impact of viral load on T cell exhaustion and the role of type I interferons is poorly understood in humans. In this research fellowship, I plan to comprehensively analyze the determinants of T cell exhaustion in the lab of Prof. E.J. Wherry. I will take advantage of mass cytometry, a novel tool that allows the simultaneous analysis of >30 different cell markers on a single cell and is thus ideally suited for the combinatorial analysis of T cell differentiation & function. In particular, I will analyze the expression of a large number of T cell differentiation markers and the co-expression of inhibitory receptors, the co-expression patterns of transcription factors, multiple T cell effector functions of exhausted virus-specific CD8+ T cells and the responsiveness of CD8+ T cells to inflammatory and regulatory molecules and inhibitory receptor blockade. The mass cytometry analysis will be combined with other established complementary state-of-the art techniques such as multiparametric polychromatic flow cytometry, transcriptomics and the use of bioinformatic tools for adequate analysis of the multidimensional information generated on single cells. These analyses will be performed in cohorts of chronically infected HBV and HCV patients and healthy controls. The role of viral load and type I interferon on the exhaustion of HCV-specific CD8+ T cells will be analyzed in unique cohorts of chronically HCV-infected patients treated interferon-free with novel direct-acting antivirals. In addition, I will analyze the impact of type I Interferon on the adaptive vaccine response to Influenza vaccination in patients with chronic HBV or HCV infection, during interferon treatment, and in healthy controls. In sum, this project should provide important insights into the determinants T cell exhaustion, T cell differentiation and the immunobiology of HBV and HCV infection and will have implications for therapeutic interventions during chronic infection.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor E. John Wherry, Ph.D.