Viral hemorrhagic fever (VHP) in humans is caused by several etiologic agents including arenaviruses, bunyaviruses, and filoviruses. These agents have been classified as category A pathogens by the NIAID because of their potential of being used for intentional exposure in acts of bioterrorism and biological warfare. In addition to the high rate of morbidity and mortality associated with these infections, clinical disease is characterized by rapid onset of symptoms and death. Therefore, there is a critical need to develop effective vaccines and immunotherapeutic strategies to combat these often-fatal infections. The Old World arenaviruses include Lassa virus and the prototypic lymphocytic choriomeningitis virus (LCMV). Similar to LCMV, CDS T cell-mediated immunity is likely to be important for defense against Lassa fever and therefore, vaccines against these agents need to elicit potent CDS T cell memory. Typically, CDS T cell responses can be divided into three distinct phases: (1) expansion phase when naive T cells get activated to undergo clonal expansion and differentiation into effector cells; (2) contraction phase when ~95% of the effector CDS T cells undergo apoptosis, and (3) memory phase during which the remaining 5% of the CDS T cells are maintained as memory T cells for extended periods of time. These memory CDS T cells confer protective immunity against re- infection by rapidly expanding and differentiating into effector cells. The development of protective immunity depends upon the generation of a critical number of memory CDS T cells, and there is high level of interest to boost the number of vaccine-induced memory T cells. Using the well-characterized mouse model of LCMV infection, we have obtained strong preliminary data that IL-7 therapy during the contraction phase of the CDS T cell response led to a substantial enhancement in the number of virus-specific memory CDS T cells. Understanding the mechanisms underlying the IL-7- induced enhancement in CDS T cell memory is the focus of this application.
The specific aims are to determine the: (1) effects of IL-7 therapy on the 'quantity' and 'quality' of long-term CDS T cell memory in both lymphoid and non-lymphoid organs using the state-of-the-art phenotypic and functional assays; (2) cellular and molecular basis of IL-7-induced enhancement of CDS T cell memory.
Specific aim 2 will be addressed by examining the effect of IL-7 therapy on the proliferation and apoptosis of LCMV-specific CDS T cells and investigating the role of BCL-2, MCL-1, and BIM in regulating IL-7-induced effects using transgenic and knockout mice. The proposed studies should aid in the rational design of vaccines that can engender potent CDS T cell memory and protect against poxvirus and arenaviral infections. ? ? ?
