The major goal of this project is to define the functions and mechanisms by which T cell costimulatory pathways regulate anti-viral immunity. To achieve this goal we are using an established model of influenza infection. Our studies indicate that one of the newer pathways in the B7:CD28 family, the PD-1: PD-1/PD-L2 pathway, delivers inhibitory signals that that play a critical role in regulating the interplay between host defenses aimed at eradicating pathogenic microbes and microbial strategies that evolved to resist immune responses The therapeutic potential of manipulating PD-1 and its ligands to enhance immune responses during infection gives impetus to further investigation of how these important immunoregulatory molecules modulate antimicrobial immunity and immunopathology. The discovery of the new PD-L1: B7-1 pathway compels us to investigate how B7-1:PD-L1 interactions are involved in regulating anti-microbial immunity, and dissect the roles of PD-L1:PD-1 vs. PD-L1:B7-1 interactions during infection.
Our specific aims are: 1: To analyze the functional significance of PD-L1:B7-1 and PD-L1:PD-1 interactions in controlling the activation and differentiation of na'i've CDS T cells. We will investigate the roles of PD-L1:B7-1 interactions, PD-L1:PD-1 interactions individually and together in controlling the CDS T activation, differentiation, and fate as memory cells or more differentiated effector cells. We will visualize the roles of these pathways in controlling activation of CDS T cells. 2. To investigate the roles of PD-L1:PD-1 and PDL1: B7-1 interactions in controlling responses of CDS effector T cells. We will dissect the roles of these pathways in controlling CDS effector T cell function. We will visualize the dynamics of the effector response in the lymph node by intravital microscopy 3 To analyze the roles of the PD-1:PD-L and PD-L1:B7-1 pathways in controlling protective immunity to influenza virus. We will evaluate how PD-L1:PD-1 and PD-L1:B7-1 interactions control activation and fates of memory T cells. We will perform challenge infection intranasally to evaluate protective immunity or s.c. to examine the dynamics of the secondary response by intravital microscopy/2 photon imaging approaches.Insights from these studies may lead to improved prophylactic and/or therapeutic vaccination strategies.
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