Project Details
Abstract
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 IDs
Project ID:PC9902-1933
External Project ID:NSC98-2320-B182-038-MY3
External Project ID:NSC98-2320-B182-038-MY3
Status | Finished |
---|---|
Effective start/end date | 01/08/10 → 31/07/11 |
Keywords
- viral infection
- CD8 T cells
- B cells
- CD8αα molecule
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.