Title

Changing antigen specificity during the CD8 recall response to secondary influenza virus infection

Date of Completion

January 2011

Keywords

Biology, Cell|Biology, Virology|Health Sciences, Immunology

Degree

Ph.D.

Abstract

Memory CD8 T cells are important entities of the Immune System that protect the host against viral infections. Their protective role does not last for extended periods of time even though circulating memory CD8 T cells can be detected for nearly two years after the infection is cleared. The role of dendritic cells (DCs) in the priming of naïve CD8 T cells has been thoroughly investigated, however their role in the reactivation of memory CD8 T cells upon secondary influenza virus infection has not been fully elucidated yet. During prolonged antigen presentation memory CD8 T cells showed a partially-activated phenotype. We hypothesized that during late antigen presentation the partially-activated memory CD8 T cells were stimulated by immature DC which provided weak costimulatory signals, thus I attempted to augment DC maturation by the use of TLR ligands to induce inflammation. I also tried to augment the CTL response by directly targeting key costimulatory molecules such as CD86, CD40, OX-40 and 4-1BB. My results showed that none of these approaches was sufficient to drive a robust response from naïve F5 cells during late antigen presentation (i.e. IFN-γ and cell proliferation). In the second part of my thesis, I examined the mechanisms that are responsible for the changing of antigen specificity during the CD8 T cell recall response to a secondary influenza virus infection. Although other investigators have addressed this question, the mechanisms that drive the reactivation of NP and PA-specific memory CD8 T cells during heterosubtypic immunity have not been fully elucidated yet.^ My data demonstrated that this change is caused by a rapid and transient migration of CD103+ DCs early after secondary infection, where they preferentially stimulated NP-specific memory CD8 T cells. In contrast CD8+ DCs stimulated both NP and PA-specific memory CD8 T cells with slightly delayed kinetics. Although CD11b+ DCs were very numerous after secondary infection, they did not reactivate NP or PA-specific memory CD8 T cells. As a whole, the results presented in this work provide new insights into the mechanisms that are responsible for the change in antigen specificity upon a secondary influenza infection and further contribute to the understanding of influenza virus immunobiology and its potential as an important source of information for vaccine development. ^