Understanding and Enhancing Cytotoxic T Lymphocytes Function for Anti-Viral Immunity

Chronic infections, such as those caused by chronic human immunodeficiency virus (HIV) hepatitis B virus (HBV), and Epstein-Barr virus (EBV), are global epidemics that lead to life-long diseases and impose significant health burdens. Cytotoxic T lymphocytes (CTLs) are a population of adaptive immune cells specialized in cytolysis of infected cells. However, CTLs fail to eliminate chronic infections in majority of cases. There are several mechanisms by which these viruses evade eradication by CTLs. One of the mechanisms commonly used by both HIV and EBV is to 'hide' inside B cell follicles in secondary lymphoid organs which contain fewer CTLs. Another strategy is to induce the exhaustion of T cells, a phenomenon which significantly reduces the CTL’s capability to eliminate viral infections. This thesis aims to tackle the chronic infections from these two angles. The thesis consists of two parts. In the first part, I describe a novel population of CTLs that are able to migrate into B cell follicles and control infections therein. In the second part, I characterised a novel monoclonal antibody that potentiates the bioactivity of an immunostimulatory cytokine, interleukin-21 (IL-21), which boosted the number and cytotoxicity of CTLs. Enhancing the follicular entry and cytotoxic activity of CTLs provide feasible therapeutic approaches to reduce viral infections, which may eventually lead to the elimination of chronic infections such as HIV, HBV and EBV.