Characterization of the CD4+ T Cell Response to Mouse Polyomavirus Infection Público
Lin, Eugene (2012)
Abstract
Virus-specific CD4+ T cells optimize anti-viral responses by
providing help for anti-viral humoral responses and CD8+ T cells.
However, little is known about the impact of low-level persistent
infections on the fate and function of virus-specific CD4+ T cells.
Using a mouse polyomavirus (MPyV) infection model, we identified
two dominant CD4+ T cell populations specific for epitopes derived
from the nonstructural LT antigen and VP1, the major viral capsid
protein. These MPyV-specific CD4+ T cells vary in terms of their
magnitude, functional profile, and phenotype during acute and
persistent phases of infection. Employing a minimally myeloablative
mixed bone marrow chimerism approach, we further show that
naïve virus-specific CD4+ T cells are primed de novo during
persistent virus infection.
After clearance of an acute viral infection, memory T cells develop
that survive in the absence of antigen and can mount robust recall
responses against challenge infection. During chronic high load
infections, however, virus-specific CD8+ T cells become dependent
on antigen for their survival. Whether T cells formed during
low-level persistent infections require antigen for their survival
is less clear. In this study, we developed a novel approach to
ablate MPyV replication during persistent infection. We generated a
recombinant MPyV in which genes critical for replication are floxed
(A2.Flx). Cre-mediated deletion of A2.Flx leads to reductions in
viral levels both in vitro and in mice expressing Cre
constitutively. Utilizing mice expressing a tamoxifen-inducible
Cre, we found that reduction of viral replication during persistent
A2.Flx infection had a variable impact on virus-specific CD4+ and
CD8+ T cells. While some MPyV-specific T cell populations were
notably reduced, others were maintained but adopted a more central
memory T cell phenotype. Our data suggests that antigen is not
necessarily required for survival of MPyV-specific memory T cells
and those cells can be redirected toward a phenotype associated
with antigen-independent survival following reductions in viral
antigen.
Table of Contents
Table of Contents
Abstract
List of Figures
Chapter 1: Introduction
I. Anti-viral immunity and CD4+ T cells
II. Persistent infection impacts T cell memory and
function
III. Polyomavirus pathogenesis
IV. Adaptive immunity to mouse polyomavirus
Chapter 2: Heterogeneity among viral antigen-specific CD4+ T
cells and their de novo recruitment during persistent polyomavirus
infection
Chapter 3: Assessing the impact of persistent infection on
polyomavirus-specific T cells
Chapter 4: Discussion
About this Dissertation
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