"Constraints on T Cell Responsiveness in Chronic Hepatitis B Virus Infection"
Dr Mala K Maini
Medical Research Council
Description of Project:
Chronic HBV infection affects over 350 million individuals worldwide and is a leading risk factor for the development of hepatocellular carcinoma. Virus clearance is immune mediated primarily by a strong multispecific CD8+ T cell response. Previous studies have well characterised marked virus specific CD8+ T cell dysfunction within these patients, however in addition, there has also been some suggestion of a global T cell impairment to mitogens and recall antigens. In this present study, we aim to 1) better characterise the nature of this non-antigen specific CD8+ T cell impairment in these patients and 2) investigate mechanisms to which this dysfunction may be attributable. Two possible mechanisms we suggest may result in this hyporesponsiveness are CD3Zeta downregulation (a proximal T cell receptor associated signalling molecule), and accelerated telomere shortening resulting in an end stage effector phenotype of these cells. Through investigating the nature of this generalised CD8+ T cell dysfunction, we may identify novel mechanisms of dysfunction within the virus specific CD8+ population, the direct study of which is hampered by extremely low circulating frequencies in these patients
C Dunn, M Brunetto, G Reynolds, T Christophides, PT Kennedy, P Lampertico, Abhishek Das, AR Lopes, P Borrow, K Williams, E Humphreys, S Afford, DH Adams, A Bertoletti, MK Maini. Cytokines induced during chronic hepatitis B virus. J Exp Med. 2007;204(3):667-80
Winner of the Cordwainers Prize 2008