The major goal of this project is to define the functions and mechanisms by which T cell costimulatorypathways regulate anti-viral immunity. To achieve this goal we are using an established model of influenzainfection. Our studies indicate that one of the newer pathways in the B7:CD28 family, the PD-1: PD-1/PD-L2pathway, delivers inhibitory signals that that play a critical role in regulating the interplay between hostdefenses aimed at eradicating pathogenic microbes and microbial strategies that evolved to resist immuneresponses The therapeutic potential of manipulating PD-1 and its ligands to enhance immune responsesduring infection gives impetus to further investigation of how these important immunoregulatory moleculesmodulate antimicrobial immunity and immunopathology. The discovery of the new PD-L1: B7-1 pathwaycompels 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 theactivation and differentiation of na'i've CDS T cells. We will investigate the roles of PD-L1:B7-1interactions, 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 ofthese 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 thesepathways in controlling CDS effector T cell function. We will visualize the dynamics of the effector responsein the lymph node by intravital microscopy 3 To analyze the roles of the PD-1:PD-L and PD-L1:B7-1pathways in controlling protective immunity to influenza virus. We will evaluate how PD-L1:PD-1 andPD-L1:B7-1 interactions control activation and fates of memory T cells. We will perform challenge infectionintranasally to evaluate protective immunity or s.c. to examine the dynamics of the secondary response byintravital microscopy/2 photon imaging approaches.Insights from these studies may lead to improvedprophylactic and/or therapeutic vaccination strategies.
Showing the most recent 10 out of 57 publications
