Arena viruses are one of the many etiologic agents of viral hemorrhagic fever (VHF) in humans. Because of the high rates of mortality and morbidity associated with these infections, and the potential of being used as agents of bioterrorism, are arenaviruses are classified under category A pathogens. At the present time, there are no vaccines to provide protection against arena viral infections in human beings. The Old World arena viruses include the Lassa virus and lymphocytic choriomeningitis virus (LCMV). Evidence indicate that cellular immunity mediated by CD8 T cells is important in defense against LCMV, and most likely Lassa virus. Therefore, vaccines against these viruses need to engender potent CD8 T cell memory. However, the mechanism(s) of induction of CD8 T cell memory are not well understood and currently, this is an area of intense investigation. Typically, CD8 T cell responses can be divided into three distinct phases: (1) the expansion phase when naive T cells undergo antigen-driven proliferation and differentiation into effector cells, (2) the contraction phase when 90-95% of the expanded T cells are eliminated, and (3) the memory phase when the remaining 5% of the expanded CD8 T cells survive for extended periods as memory T cells. The number of memory CD8 T cells generated is dependent upon the extent of expansion and the magnitude of contraction. Since protective immunity is dependent upon the induction of a threshold number of memory CD8 T cells, it is critical to gain a thorough understanding of the mechanisms that regulate the expansion and contraction phases of the T cell response. Using the well-characterized LCMV model in mice, we have obtained strong preliminary data that IFNgamma receptor (IFNgammaR) signaling plays an important role in limiting the number of antigen-specific memory CD8 T cells that survive the contraction phase of the T cell response. Based on this a strong case can be made to modulate IFNgammaR signaling to augment the number of memory CD8 T cells during vaccination. Understanding the mechanisms underlying the regulation of LCMV-specific CD8 T cell response by IFNgammaR is the focus of this proposal.
The specific aims are: (1) To determine the importance of IFNgammaR expressed on T cells vs. non-T cells in regulating CD8 T cell responses in vivo by utilizing TCR transgenic mice, bone marrow chimeric mice, and IFN( unresponsive transgenic T cells, (2) To investigate the importance of temporal and spatial control of IFNgammaR signaling in the regulation of the contraction phase of LCMV-specific CD8 T cell response by antibody blocking experiments and by developing a transgenic mouse model in which IFNgammaR expression in T-cell lineage can be turned on and off at will, and (3) To determine the effect of IFNgammaR deficiency on the qualitative and functional attributes of LCMV-specific memory CD8 T cells. These studies should aid in the development of vaccines against arena viruses in particular and other viruses in general.
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