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
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
|Subfield / Discipline|
|Committee Chair / Thesis Advisor|
|Characterization of the CD4+ T Cell Response to Mouse Polyomavirus Infection ()||2018-08-28||