In this proposal, we plan to explore some of the consequences that arise when individuals with a limited or skewed CD8" T cell TCR repertoire encounter novel pathogen epitopes. Our focus is on the role of TCR affinity for its MHC/peptide ligand in driving the CDS response. We postulate that the apparent failure of immune compromised animals to mount a robust peak response may obscure a low avidity CD8+ T cell response that occurs but is missed by the usual ways of performing tetramer staining, target killing, and intracellular cytokine staining (ICS). The goal of the project is to discover whether immune-compromised animals (such as aged, or animals recovered from lymphoid ablation therapies) mount low avidity CDS responses, how these T cells are controlled, how tightly they must recognize the pathogen to contribute to immunity, and how they influence the outcome of infection.
SPECIFIC AIM 1. To characterize the phenotype, function and genetic signature of TCR transgenic CD8+ T cells responding in vivo to infection with a pathogen expressing either a high or a low affinity TCR ligand. For these experiments, we have generated a number of recombinant strains of the bacterial pathogen, Listeria monocytogenes, which secrete hen Ovalbumin (Ova) containing either the wild-type peptide (SIINFEKL) recognized by the OT-1 TCR, or single residue variants (altered peptide ligands) that interact less well with this TCR while binding equally well to the relevant H2-Kb MHC class I molecule.
SPECIFIC AIM 2. To assess the protection provided by T cells with a relatively low avidity for pathogen epitopes. Protection against a challenge infection with Listeria monocytogenes expressing a range of altered peptide ligands recognized by TCR transgenic cells will be assayed in these experiments.
SPECIFIC AIM 3. To determine the functional avidity of T cells responding to infection in mice with limited TCR repertoires and the consequences for immune protection. Limited repertoires will be generated in a number of ways including use of old mice, thymectomized mice, in some cases primed with pathogens such as lymphocytic choriomeningitis virus (LCMV) that evoke large effector and memory CD8+ T cell responses, and mice recovering from lymphoid ablation. Infection with pathogens that are either unrelated or crossreactive with previously encountered pathogens will be used.
With increasing age and following certain therapies, the immune system is unable to mount a successful defense against infections. Part of this failure is due to a loss of antigen-reactive diversity in the pool of T cells. We aim to explore how this deficiency impacts adaptive immunity to pathogens.
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