Memory T cells (Tm) are present in small quantities in a host. Upon re-encountering pathogens, Tm could respond rapidly to increase the number and to differentiate into effector cells as a way to generate a potent adaptive immunity. In this proposal, we will study a new phenomenon that small numbers of Tm cells could be selectively expanded into large quantities by stimulation through ligation of CD137 molecule without re- exposure to antigen. More importantly, proliferation of Tm cells by CD137 stimulation is accompanied by acquisition of innate immunity function to pathogens. In this proposal, we will extend our observation to address fundamental issues which will be critical for future application of Tm-mediated innate immunity in biodefense. A central hypothesis to be tested is that activation of Tm by CD137 stimulation could induce potent innate immunity against pathogen infection and could be developed potentially as a mean for biodefense. We will first address basic features of Tm-mediated innate immunity including molecular basis of selective activation of Tm by CD137, kinetics of innate immunity and transition of innate to adaptive immunity, using Listeria monocytogenes (LM) as a model pathogen. We will also test hypothesis in vivo that CD 137 stimulation directly activates subset Tm to produce IFN-gamma and other soluble and cell surface molecules, leading to activation of macrophages and other effector cells to eliminate LM infection. In addition, we will delineate cellular and molecular components of Tm-mediated innate immunity, as well as understanding of signal transduction events of CD137 signaling in Tm. Finally we will extend our findings to determine therapeutic potential of this method, test the role of CD137 stimulation in the elimination of LM, infection in elder animals, an immunologically compromised population as well as potential side effect of this treatment. These studies will not only establish the role of CD137 signal in Tm growth and functional maturation, but also form the foundation for future development of new approaches in biodefense against pathogens.
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