Roles of B Cell and Tcr Co-Receptor Cd8alpha Alpha in Virus Infection-Mediated Cd8 T Cell Proliferation and Differentiation

Viral infection is the serious problem in clinic for the whole world. In the past decades, we have witnessed the emergence acute or persistent viral infections in Taiwan caused by hepatitis viruses, human immunodeficiency virus, human T cell leukemia virus, papillomavirus, Epstein-Barr virus, dengue virus, SARS coronavirus, and entrovirus. Still, we continue to exposure in re-emergence of a 1918 influenza virus (avian flu, H5N1). Two major infection types are found in viral infection: acute and persistent infection. In acute infection, the CD8 T cell response to infection is highly dynamic, beginning with a cytokine-mediated attrition in memory CD8 T cell number in the early phase of infection (lymphopenic phase). This is followed by a dramatic expansion in number of virus-specific T cells (expansion phase) and then by a second decline associated with T cell apoptosis (contraction phase) and with the conversion into memory T cells that long lived after the acute infection (memory phase). Upon re-expose with the same pathogen, these memory T cells are able to rapidly proliferate and then provide a protective response (recall phase). For persistent viral infection, virus induces clonal exhaustion in virus specific CD8 T cells (exhausted phase). Obviously, the quality of CD8 T cell response is the key point for determination of the infected patterns. The definition for quality is including the number of CD8 T cells, the ability of expression of cytokine, chemokine, the ability of de-granulation and the expression of survival molecules. So, the factors which influence the CD8 T cell quality are the critical matter for prevention and therapy for viral infection. So far, not many extrinsic and intrinsic factors that modulate these different phases of T cell responses are known in past decades due to the limitation of study model and approach techniques. Using Lymphocytic choriomeningitis virus (LCMV) as model system of acute and persistent infection, we and others successfully identified PD-1 as an inhibitory receptor for generation of functional memory CD8 T cells upon viral infection in our previous study. So, using newly developing approaches (such as CDR3 spectratyping, MHC class I tetramer, well known viral peptides, in vivo killing assay and TCR transgenic mice) and B cell knockout and CD8αm3 transgenic mice as model system, we would like to reveal more factors involved in CD8 T response upon viral infection in this grant. In this proposal, we want to investigate the roles of naïve B cells, TCR co-receptor CD8αα, microRNA in each phase of T cell responses in detail upon LCMV infection. In our preliminary data, we found that un-functional TCR co-receptor CD8αα did not influence the viral specific CD8 T cells responses against virus infection in CD8αm3 transgenic mice, comparing to WT B6 mice. Of note, impaired expansion of CD8αα LCMV-specific CD8 T cells was demonstrated during recall responses in CD8αm3 transgenic mice. In addition, we found that B cells not only can be the antibody producer and antigen presenter but also the determinants for CD8 T cell response. Data from our preliminary study indicated that B cells can strongly associate with a subset of antigen-specific CD8 T cells as doublets during viral infection. Using B-cell knockout mice, we showed that the biological functions of memory CD8 T cells are impaired in the absence of B cells. Another factor that may govern the T cell responses is microRNA. We performed the microRNA microarray with naïve and LCMV-responsive CD4 and CD8 effector T cells. In addition, the interplay between microRNA, CD8 T cells, and persistent infection will be explored by infected the mice with LCMV variant cl-13. We plan to identify the multiple factors regulate the T cell activation and memory formation, and reveal their mechanisms. The more we understand the mechanisms involved in controlling the determination of CD8 T cell response during viral infection, the more we can develop the effective agents for viral prevention and viral therapy. So, the findings of this three-year grant will provide useful information for a better design of therapeutic drugs, preventive vaccines and immunotherapy protocols.

Project ID:PC10001-0266
External Project ID:NSC98-2320-B182-038-MY3