Costimulatory requirements of helpindependent anti-influenza CTL

© 2012 Dr. Shirley Seah Gek KhengThis thesis focused on the role of costimulatory molecules, CD28 and CD40L, on the induction and expansion of help-independent CD8+ T cell response during primary influenza virus infection. It has been conventionally believed that the help provided by CD4+ T cells is mediated by CD40-CD40L interactions, which results in the licensing of DCs. However, during some infections such as influenza virus infection, CD8+ T cell responses can be mounted without the requirements of CD4+ T cell help. Although there have been numerous studies on the role of costimulation in CD8+ T cell immunity, many were done in the presence of CD4+ T cells. Hence it is difficult to distinguish which T cell subset (CD4+ or CD8+ T cell), or both, the costimulation has had an impact on. This thesis has dissected the role of CD28 and CD40L costimulation on the activation and expansion of help-independent CD8+ T cells during primary influenza infection. This thesis demonstrated that, unlike CD4+ T cell help, the generation of influenza-specific CD8+ T cells was dependent on the direct costimulation of CD28 and CD40L. The impaired generation of influenza-specific CD8+ T cells in the absence of CD28 costimulation, and CD40L costimulation to a lesser extent, correlated with virus titre in the lungs. In addition, this thesis also demonstrated that CD28 costimulation was required in the early activation of “helpless” influenza-specific CD8+ T cells. In contrast, the CD40L costimulation was required at the late phase of the primary response, suggesting the role of CD40L costimulation in the expansion of “helpless” CD8+ T cells, after the initial activation by CD28 costimulation. In vitro studies revealed that CD80/86 and CD40L on DCs were important for the priming of “helpless” CD8+ T cells. Correlating with in vivo studies, CD28-CD80/86 costimulation was required for the early activation of CD8+ T cells, while CD40- CD40L costimulation was required at the late phase for the expansion of CD8+ T cells. CD28-CD80/86 costimulation had also been demonstrated to promote the survival of CD8+ T cells