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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI081680-05
Application #
8436317
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$379,447
Indirect Cost
$65,592
Name
Oregon Health and Science University
Department
Type
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Smith, Jessica L; Stein, David A; Shum, David et al. (2014) Inhibition of dengue virus replication by a class of small-molecule compounds that antagonize dopamine receptor d4 and downstream mitogen-activated protein kinase signaling. J Virol 88:5533-42
Trobaugh, Derek W; Gardner, Christina L; Sun, Chengqun et al. (2014) RNA viruses can hijack vertebrate microRNAs to suppress innate immunity. Nature 506:245-8
Haick, Anoria K; Rzepka, Joanna P; Brandon, Elizabeth et al. (2014) Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology. J Gen Virol 95:578-90
Gibbs, David L; Gralinski, Lisa; Baric, Ralph S et al. (2014) Multi-omic network signatures of disease. Front Genet 4:309
Gardner, Christina L; Hritz, Jozef; Sun, Chengqun et al. (2014) Deliberate attenuation of chikungunya virus by adaptation to heparan sulfate-dependent infectivity: a model for rational arboviral vaccine design. PLoS Negl Trop Dis 8:e2719
Josset, Laurence; Tchitchek, Nicolas; Gralinski, Lisa E et al. (2014) Annotation of long non-coding RNAs expressed in collaborative cross founder mice in response to respiratory virus infection reveals a new class of interferon-stimulated transcripts. RNA Biol 11:875-90
Nikolich-┼Żugich, Janko (2014) Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J Immunol 193:2622-9
Engelmann, Flora; Josset, Laurence; Girke, Thomas et al. (2014) Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model. PLoS Negl Trop Dis 8:e3295
Pal, Pankaj; Fox, Julie M; Hawman, David W et al. (2014) Chikungunya viruses that escape monoclonal antibody therapy are clinically attenuated, stable, and not purified in mosquitoes. J Virol 88:8213-26
Fontaine, Krystal A; Camarda, Roman; Lagunoff, Michael (2014) Vaccinia virus requires glutamine but not glucose for efficient replication. J Virol 88:4366-74

Showing the most recent 10 out of 75 publications